August Longevity Update

Hello and welcome once again to this month’s longevity update. After an uber-busy summer work wise, I’m back to famine (such is the life of a contract teacher), but at least it means I can devote more time to longevity and get these newsletters sent out more promptly!

I’ve been asked by a few people how my longevity regimen is working out, and truth be told I have absolutely no idea! I have not noticed or felt anything, and the grey hairs on my beard have not magically reversed back to black. But, then again, I wasn’t expecting to as I already lead a fairly healthy lifestyle (daily fasting, healthy diet & plenty of movement), and haven’t yet felt the physical or mental effects of ageing. I have been taking some basic biomarkers (weight, blood pressure & blood glucose), so maybe once I get around to analyzing them some trend will emerge. Basically, I’m trusting in the science and hope that my regimen will provide benefit in the long term.

I had however hoped to pass on some anecdotal results via my parents, who being in their late seventies, could potentially see some noticeable results. Unfortunately, despite having all the necessary supplements & detailed instructions since June, they had not started yet (“once we’re back from holiday; once the patio is done; once etc etc…”). I finally lost it a couple of days ago and had to be quite brutal to them. I told my mom I wouldn’t speak to her again until she started and asked my dad how much he had enjoyed her stroke last year and if he was looking forward to the next one. He was quite understandably shocked, but it did the trick and they started that very same day! I will provide an anecdotal update in a few months time.

In the meantime, I’ve added a few sections to the end of the supplementary information, as there is so much exciting news out there and I didn’t want to clog up the round-up section. The new sections concern cellular reprogramming, young blood factors and miscellaneous, where you can find stuff on stem cells, ageing theories & how optimists live longer!

Follow me on Twitter @ChrisPollyanna1 for the latest updates! (after a two month hiatus… )

Finally – please feel free to forward this email to anyone who might be interested, and please let me know if anyone would like to be included in my mailing list! Also, any feedback is greatly appreciated… J
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NOTE: I’ve been having trouble linking to the science journal hacking site www.sci-hub.tw , so am only including Full Text links to articles not behind a paywall. I have still been able to download most of them, so if there are any that you are after, I can send them upon request, or you can simply copy the paper’s URL into the site above to get +95% of papers hidden behind paywalls.

August Round-Up:

• This exciting study is the first to try to recapitulate the benefits of young blood via the modulation of a couple of blood factors which change with age. Because ageing is a multi-factoral condition, scientists need to combine treatments, and the great thing about this study is that they do so. Also the two drugs used are already FDA approved, which means that translation to the clinic should be easier. Notwithstanding the additional benefit of not needing young blood in the first place! Rejuvenation of brain, liver and muscle by simultaneous pharmacological modulation of two signaling determinants, that change in opposite directions with age. Full Text

In the same vein (pardon the pun) the following announcement is from a company which uses a proprietary fraction of young blood plasma to try to treat age related conditions. The promising top-line results here are for Alzheimer’s (full results to be presented at a conference in December): Alkahest Announces Positive Top-line Data from Phase 2 Study in Mild to Moderate Alzheimer’s Disease

• Rather than looking at the benefits of young blood in an aged animal, the following study looked at young bone marrow (containing stem cells) transplanted into old mice and the effects on heart attack recovery. The results showed an improvement in recovery after an induced heart attack, as well as a reduction in cardiac senescent cell burden and a degree of rejuvenation: Long-term repopulation of aged bone marrow stem cells using young Sca-1 cells promotes aged heart rejuvenation. Full Text

• Fascinating article (I learnt a lot) about a class of drugs which can help ageing by preventing or reversing detrimental changes to the epigenome. If you are following a ketogenic diet or “keto” for short, then this might be the mechanism behind its health benefits, as keto bodies turn out to be HDAC inhibitors: From molecular promise to preclinical results: HDAC inhibitors in the race for healthy aging drugs. Full Text

• Another potential mechanism for improving longevity is to increase our telomeres (protective caps at the end of our chromosomes) via activating the enzyme telomerase. This paper looks at various nutrients which do so – main take away: olive oil is very good for you! Discovery of potent telomerase activators: Unfolding new therapeutic and anti-aging perspectives. Full Text

• For those of you lamenting the need for reading glasses, here is a phase I/II study of some eye drops which reverse the stiffening of the eye and improve near vision: Clinical Trial of a Cross-Link Breaker to Treat Presbyopia in the Aging Eye Treating presbyopia with an eye drop?

• Finally, the current issue of MIT Technology Review is devoted to longevity - Old Age Is Over! – if you want it with some very interesting articles (LEAF commentary). Unless you buy a copy or subscribe digitally, you are only allowed to access three articles per month. Here are my three recommendations:

Has this scientist finally found the fountain of youth?, about partial epigenetic reprogramming, the leading story from last month’s update.

The anti-aging drug that’s just around the corner, about the Rapamycin analogue mentioned last month (I can’t let a month go by without mentioning Rapamycin, can I?).

The transhumanists who want to live forever, about the biohackers taking matters into their own hands.

An eloquent polemic about ageing and what we should do about it by Reason, the author of the blog Fight Aging!, which I read on a daily basis (& whom I got to meet at the conference in July). The longevity field is roughly divided into two camps, those who think that it is programmed and those who think that it is the result of wear & tear damage. He is firmly in the damage camp. As a counterpoint, underneath is the programmed ageing view as espoused by Josh Mittledorf, another blogger I follow (& met as well), in relation to the cellular reprogramming study talked about last month.
YouTube link
Fight Aging! Link with transcript
Josh’s indirect response:
https://joshmitteldorf.scienceblog.com/2019/07/30/rejuvenation-at-the-cell-level/
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Further sources of information:
Fight Aging! (run by the gentleman in the video above, quite opinionated about the damage theory of ageing)
Life Extension Advocacy Foundation (LEAF) (best source of longevity information on the web)
Longecity (good forums where the self-experimenters reside!)
Aging Matters (good blog from the programmed ageing side)
Research Institutes:
SENS Research Foundation (I have a recurring monthly donation)
Buck Institute

Private initiatives:
Age-Reversal Network (good information & forums for those interested in self-experimentation – this is where I found how to get non-prescription Rapamycin)
Better Humans
Gerontology Research Group
Lifespan.io (Tied together with LEAF, I have a recurring monthly donation)

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August Supplemental Information

***Disclaimer 1 – As should be self-evident to anyone receiving these emails, I am NOT a doctor or indeed a scientist. All the information pertained within is for information purposes only; use at your own risk. Please consult with a healthcare practitioner if needing medical advice.***

**Disclaimer 2 – In no way should supplements be a replacement for an unhealthy diet or lifestyle. A varied, plant dominant dietary pattern is the cornerstone for health. Try to eat the rainbow – the greater the variety, the greater the benefit. Even though I might take a supplement derived from a plant source, I still eat the plant in question. Also, make sure you move as much as possible – that is what we evolved to do.**

*Also bear in mind that most of the studies mentioned below are in rodents, not humans. Rodents, needless to say, do not always react the same way to drugs as humans do – witness the countless times cancer or another disease has been cured in rodents only to subsequently fail human trials. I have *bolded any human trials.*
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Lifestyle

Fasting/Dietary Restriction – certainly the cheapest & also one of the most effective anti-ageing interventions currently available. It comes in many flavours, but I fast for at least 12 hours every day.
*Alternate Day Fasting Improves Physiological and Molecular Markers of Aging in Healthy, Non-obese Humans. Full Text
*Recurrent circadian fasting (RCF) improves blood pressure, biomarkers of cardiometabolic risk and regulates inflammation in men. Full Text
Short-term dietary restriction in old mice rejuvenates the aging-induced structural imbalance of gut microbiota. Full Text
Comparison of glycemic improvement between intermittent calorie restriction and continuous calorie restriction in diabetic mice Full Text

Diet – let food be thy medicine…
*Health Benefits of Nut Consumption in Middle-Aged and Elderly Population Full Text
*Diet Quality Is Associated With Mortality in Adults Aged 80 Years and Older: A Prospective Study.
*Adherence to a Mediterranean diet is associated with cognitive function in an older non-Mediterranean sample: findings from the Maine-Syracuse Longitudinal Study.
*Coffee Consumption and Risk of Atrial Fibrillation in the Physicians' Health Study Full Text

Exercise – if you could bottle the benefits of exercise, it would be the biggest blockbuster drug of all time.
*Dose-response associations between accelerometry measured physical activity and sedentary time and all cause mortality: systematic review and harmonised meta-analysis. Full Text
*Isometric handgrip training reduces blood pressure and wave reflections in East Asian, non-medicated, middle-aged and older adults: a randomized control trial.

Non-prescription Supplements (in alphabetical order)

Astaxanthin – which is behind the pink colour of salmon & shrimp. Considered the most powerful carotinoid, it has anti-oxidative, anti-inflamatory, anti-cancer, neuro-protective and skin-protective qualities. I take 4mg daily.
Effects of astaxanthin onaxonal regeneration via cAMP/PKA signaling pathway in mice with focal cerebral infarction
Therapeutic and Protective Effects of Liposomal Encapsulation of Astaxanthin in Mice with Alcoholic Liver Fibrosis Full Text
Can krill oil be of use for counteracting neuroinflammatory processes induced by high fat diet and aging?

Curcumin – the spice which gives curries their yellow colour. Anti-inflammatory and neuroprotective. I take 1 gram a day. Needs to be taken with black pepper (piperine) to improve bio-availability.
Curcumin and Type 2 Diabetes Mellitus: Prevention and Treatment. Full Text
*Postprandial Responses of Serum Bile Acids in Healthy Humans after Ingestion of Turmeric before Medium/High-Fat Breakfasts
*The effects of curcumin supplementation on endothelial function: A systematic review and meta-analysis of randomized controlled trials.
The Autophagy Signaling Pathway: A Potential Multifunctional Therapeutic Target of Curcumin in Neurological and Neuromuscular Diseases. Full Text
*Curcumin for depression: a meta-analysis.
*Oral Curcumin No More Effective Than Placebo in Preventing Recurrence of Crohn's Disease After Surgery in a Randomized Controlled Trial.

Fisetin – a flavonoid found in highest concentration in strawberries. Senolytic, anti-inflammatory, anti-cancer, neuro-protective & Sirt1 activator. I take 100mg daily.
Fisetin Suppresses the Proliferation and Metastasis of Renal Cell Carcinoma through Upregulation of MEK/ERK-Targeting CTSS and ADAM9. Full Text

Nicotinamide MonoNucleotide (NMN) – newer NAD+ precursor. I take 250mg daily.
Impacts of obesity, maternal obesity and nicotinamide mononucleotide supplementation on sperm quality in mice Full Text
Corneal Denervation Causes Epithelial Apoptosis Through Inhibiting NAD+ Biosynthesis Full Text
Nicotinamide mononucleotide (NMN) supplementation promotes anti-aging miRNA expression profile in the aorta of aged mice, predicting epigenetic rejuvenation and anti-atherogenic effects.

Nicotinamide Riboside (NR) – NAD+ precursor.
*Effects of nicotinamide riboside on endocrine pancreatic function and incretin hormones in obese, non-diabetic men
*Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures. Full Text
Why Is Mom Stressed: Homeorhesis as the Potential Problem and Nicotinamide Riboside as the Potential Solution. Full Text
Supplementation with Nicotinamide Riboside Reduces Brain Inflammation and Improves Cognitive Function in Diabetic Mice. Full Text

Pterostilbene – found in blueberries. Anti-oxidant, anti-inflamatory and Sir1 activator. Similar to, but with greater bioavailability than resveratrol. Just started taking 50mg again daily. Works better in conjunction with NAD+ precursors.
Pterostilbene inhibits lung squamous cell carcinoma growth in vitro and in vivo by inducing S phase arrest and apoptosis. Full Text

Resveratrol – found in the skin of grapes. Anti-oxidant, anti-inflamatory and Sir1 activator. Just started taking 250mg a day. Works better in conjunction with NAD+ precursors & Spermidine.
*Acute resveratrol supplementation in coronary artery disease: towards patient stratification.
Effect of resveratrol on adipokines and myokines involved in fat browning: perspectives in healthy weight against obesity. Full Text
Resveratrol rescues tau-induced cognitive deficits and neuropathology in a mouse model of tauopathy.
Resveratrol prevents chronic intermittent hypoxia-induced cardiac hypertrophy by targeting the PI3K/AKT/mTOR pathway.

Spermidine – found in wheat germ and a potent inducer of autophagy, it works in synergy with Resveratrol. I try to eat a couple of tablespoons of wheat germ every day.
Polyamines Control eIF5A Hypusination, TFEB Translation, and Autophagy to Reverse B Cell Senescence Full Text

Prescription Supplements & Extra

Rapamycin (sirolimus) – first drug proven to increase the health & lifespan of mice. Currently used for organ transplantation and against cancer. Taking 5mg once a week.
Hypothalamic mTORC2 is essential for metabolic health and longevity. Full Text
Fasting and rapamycin: diabetes versus benevolent glucose intolerance. Full Text
Local intra-articular injection of rapamycin inhibits NLRP3 activity and prevents osteoarthritis in mouse DMM models.
Neuronal TORC1 modulates longevity via AMPK and cell nonautonomous regulation of mitochondrial dynamics in C. elegans. Full Text
Activation of mTORC1 in fibroblasts accelerates wound healing and induces fibrosis in mice.
Rapamycin protects aging muscle Full Text
Rapamycin attenuates Tc1 and Tc17 cell responses in cigarette smoke-induced emphysema in mice.
Rapamycin ameliorates immune-mediated aplastic anemia by inhibiting the proliferation and metabolism of T cells.
Regulation of YAP by Mammalian Target of Rapamycin Complex 1 in Endothelial Cells Controls Blood Pressure Through COX-2/mPGES-1/PGE2 Cascade

Senolytics – not supplements or available now, but the most exciting area of anti-research at the moment. I intend to take the plunge into senolytics within the next year, before giving them to my parents:
Removing Dysfunctional Microglia Prevents Amyloid-β Plaques Full Text
Cellular senescence: at the nexus between ageing and diabetes. Full Text
Targeting p16-induced senescence prevents cigarette smoke-induced emphysema by promoting IGF1/Akt1 signaling in mice. Full Text
Targeting normal and cancer senescent cells as a strategy of senotherapy
Cortical neurons develop a senescence-like phenotype promoted by dysfunctional autophagy. Full Text
Mitochondrial metabolic reprograming via BRAF inhibition ameliorates senescence.

Epigenetic Cellular Reprogramming – the next big thing in longevity science as far as I am concerned & the closest thing we might have to a silver bullet against ageing. It involves targeting the epigenome:
Inducing Pluripotency Through Multiple Routes Full Text
Epigenetic Changes as a Target in Aging Haematopoietic Stem Cells and Age-Related Malignancies Full Text
Age-Related DNA Methylation Changes: Potential Impact on Skeletal Muscle Aging in Humans. Full Text
Screening for genes that accelerate the epigenetic aging clock in humans reveals a role for the H3K36 methyltransferase NSD1. Full Text
*Exploring Epigenetic Age in Response to Intensive Relaxing Training: A Pilot Study to Slow Down Biological Age Full Text

Young Blood Factors – another potential “silver bullet” against ageing based on the discovery that young blood seems to rejuvenate older animals and vice versa. The race is on to discover what components in blood cause these changes and if they can be applied to humans:
*Soluble Intercellular Adhesion Molecule-1 (sICAM-1) as a Biomarker of Vascular Cognitive Impairment in Older Adults
Circulating factors in young blood as potential therapeutic agents for age-related neurodegenerative and neurovascular diseases
Young Blood Rescues the Cognition of Alzheimer's Model Mice by Restoring the Hippocampal Cholinergic Circuit.

Odds & Sods
A meta-analysis of genome-wide association studies identifies multiple longevity genes. Full Text
Vitamin K as a Powerful Micronutrient in Aging and Age-Related Diseases: Pros and Cons from Clinical Studies. Full Text
Optimism is associated with exceptional longevity in 2 epidemiologic cohorts of men and women.
Rejuvenating Strategies of Tissue-specific Stem Cells for Healthy Aging Full Text
Revamping the Evolutionary Theories of Aging Full Text
Toward a unified theory of aging and regeneration Full Text
Recent advances in understanding the mechanisms determining longevity. Full Text
Reducing Gut Dysbiosis Partially Alleviates Alzheimer’s Symptoms

July Longevity Update

Hello and welcome once again to this month’s longevity update. I’ve just had the busiest summer ever teaching-wise. So busy, that I couldn’t even follow the latest longevity developments. Therefore it was quite novel, when I sat down to compile this update, to have almost no idea what transpired during July. Needless to say, a lot did, including a result I’ve been waiting for since David Sinclair sent some cryptic tweets last summer.

As mentioned in the last update, I volunteered at Ending Age-Related Diseases in New York, which was the highlight of my summer. It wasn’t so much finding out the latest news which made it great; it was the feeling of participation and meeting so many wonderful people. After having spent so much time communicating with other enthusiasts only via computer, it was refreshing to finally be surrounded by like-minded people. I highly recommend attending next year’s conference, or any other longevity related conference – a list of which can be found here. If you’re curious to read more about it, here’s the official write up & the view from Fight Aging!

Follow me on Twitter @ChrisPollyanna1 for the latest updates! (after a two month hiatus… )

Finally, any feedback is greatly appreciated… J
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NOTE: I’ve been having trouble linking to the science journal hacking site www.sci-hub.tw , so am only including Full Text links to articles not behind a paywall. I have still been able to download most of them, so if there are any that you are after, I can send them upon request, or you can simply copy the paper’s URL into the site above to get +95% of papers hidden behind paywalls.

July Round-Up:

• The cryptic tweets mentioned were about the promise of cellular reprogramming, whereby the age of a cell gets reverted back to youthfulness by the introduction of genetic factors. I strongly believe that this area is going to explode in the next few years and is the closest thing we have to a “silver bullet” against ageing. In the present study, which has not been peer reviewed yet, they were able to re-grow the optic nerve of mice – something hitherto impossible: Reversal of ageing- and injury-induced vision loss by Tet-dependent epigenetic reprogramming

• An interesting study where they took a gene associated with longevity among centenarians and gave it to a group of mice. This resulted in the mice having a reduction in the hardening of their arteries: Single systemic transfer of a human gene associated with exceptional longevity halts the progression of atherosclerosis and inflammation in ApoE knockout mice through a CXCR4-mediated mechanism. Full Text

• Telomeres, the protective caps at the end of our chromosomes, have been the subject of intense debate in the ageing community: is their length and reduction over time a symptom or a cause of ageing? So far the results have been inconclusive, but the following animal comparative study sheds some new light. It turns out that it is not the length of the telomere which predicts a species lifespan, it is the rate of shortening (of course this doesn’t tell us about cause and effect): Telomere shortening rate predicts species life span. Full Text LEAF Summary & an interview with the author, who was a headline speaker at the conference.

• It’s been just over 30 years since the modern field of ageing research started and the following review, from the leading lights of the field, provides an overview of the progress made so far, as well as arguing that we have now reached an inflection point whereby we can start to translate our understanding into treatments to increase human healthspan: From discoveries in ageing research to therapeutics for healthy ageing

• And finally, two articles about my favourite available longevity drug: Rapamycin. OK, the first article is not about Rapamycin – it’s about a similar drug, working on the same pathway, which is currently in human clinical trials. Rapamycin is now off-patent, so pharma can’t make big bucks off it, however, with this “new” drug, they can charge whatever they want! It is still significant though, for if it gains approval in a couple of years, it will be the first true anti-ageing drug on the market: Can a Single Pill Keep You Healthy to 100? For those unwilling to wait a few years to be charged an exorbitant fee, there is always generic Rapamycin, and the second article is about the men (the article is from Men’sHealth), who like me, have followed this second path: This Obscure, Potentially Dangerous Drug Could Stop Aging This is a surprisingly excellent article, featuring the same doctor I got a prescription from, as well as an honest assessment of the potential drawbacks and benefits.

YouTube Channel:
https://www.youtube.com/playlist?list=PLgiu-UInAXMPDy_P0dPYWUlg0vaKtO1Re

Facebook Channel:
https://www.facebook.com/lifespanio/videos/2018828314884987/
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Further sources of information:
Fight Aging!
Life Extension Advocacy Foundation (LEAF)
Longecity (good forums where the self-experimenters reside!)

Research Institutes:
SENS Research Foundation (I have a recurring monthly donation)
Buck Institute

Private initiatives:
Age-Reversal Network (good information & forums for those interested in self-experimentation – this is where I found how to get non-prescription Rapamycin)
Better Humans
Gerontology Research Group
Lifespan.io (Tied together with LEAF, I have a recurring monthly donation)
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July Supplemental Information

**Disclaimer 2 – In no way should supplements be a replacement for an unhealthy diet or lifestyle. A varied, plant dominant dietary pattern is the cornerstone for health. Try to eat the rainbow – the greater the variety, the greater the benefit. Even though I might take a supplement derived from a plant source, I still eat the plant in question. Also, make sure you move as much as possible – that is what we evolved to do.**

*Also bear in mind that most of the studies mentioned below are in rodents, not humans. Rodents, needless to say, do not always react the same way to drugs as humans do – witness the countless times cancer or another disease has been cured in rodents only to subsequently fail human trials. I have *bolded any human trials.*
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Lifestyle

Fasting/Dietary Restriction – certainly the cheapest & also one of the most effective anti-ageing interventions currently available. It comes in many flavours, but I fast for at least 12 hours every day.
*2 years of calorie restriction and cardiometabolic risk (CALERIE): exploratory outcomes of a multicentre, phase 2, randomised controlled trial.
*Caloric restriction, longevity and aging: Recent contributions from human and non-human primate studies.

Diet – let food be thy medicine…
*A Vitamin D, Calcium and Leucine-Enriched Whey Protein Nutritional Supplement Improves Measures of Bone Health in Sarcopenic Non-Malnourished Older Adults: The PROVIDE Study. Full Text
*Prospective Associations of Diet Quality With Incident Frailty in Older Adults: The Health, Aging, and Body Composition Study. Full Text
*Acute Supplementation with Nitrate-Rich Beetroot Juice Causes a Greater Increase in Plasma Nitrite and Reduction in Blood Pressure of Older Compared to Younger Adults. Full Text
*Alcohol Consumption in Later Life and Mortality in the United States: Results from 9 Waves of the Health and Retirement Study.
*A Mediterranean Diet with Fresh, Lean Pork Improves Processing Speed and Mood: Cognitive Findings from the MedPork Randomised Controlled Trial. Full Text
*Is there a relationship between chocolate consumption and symptoms of depression? A cross-sectional survey of 13,626 US adults Full Text
Recent Research on the Health Benefits of Blueberries and Their Anthocyanins Full Text
Alcohol in the Aging Brain - The Interplay Between Alcohol Consumption, Cognitive Decline and the Cardiovascular System. Full Text

Exercise – if you could bottle the benefits of exercise, it would be the biggest blockbuster drug of all time.
*Aerobic and resistance exercise training reverses age-dependent decline in NAD+ salvage capacity in human skeletal muscle. Full Text
*Chronic Fish Oil Consumption with Resistance Training Improves Grip Strength, Physical Function, and Blood Pressure in Community-Dwelling Older Adults. Full Text
*The Role of Muscle Mass Gain Following Protein Supplementation Plus Exercise Therapy in Older Adults with Sarcopenia and Frailty Risks: A Systematic Review and Meta-Regression Analysis of Randomized Trials. Full Text
Antiaging Effects of Aerobic Exercise on Systemic Arteries Full Text
The Impact of Different Types of Exercise Training on Peripheral Blood Brain-Derived Neurotrophic Factor Concentrations in Older Adults: A Meta-Analysis.

Non-prescription Supplements (in alphabetical order)

Astaxanthin – which is behind the pink colour of salmon & shrimp. Considered the most powerful carotinoid, it has anti-oxidative, anti-inflamatory, anti-cancer, neuro-protective and skin-protective qualities. I take 4mg daily.
*Effects of astaxanthin on VEGF level and antioxidation in human aqueous humor: difference by sex. Full Text
Do We Utilize Our Knowledge of the Skin Protective Effects of Carotenoids Enough? Full Text
The Neuroprotective Effects of Astaxanthin: Therapeutic Targets and Clinical Perspective. Full Text

Curcumin – the spice which gives curries their yellow colour. Anti-inflammatory and neuroprotective. I take 1 gram a day. Needs to be taken with black pepper (piperine) to improve bio-availability.
*Eight Weeks of a High Dose of Curcumin Supplementation May Attenuate Performance Decrements Following Muscle-Damaging Exercise. Full Text
*Curcumin and inflammation in non-alcoholic fatty liver disease: a randomized, placebo controlled clinical trial. Full Text
*Bio-optimized Curcuma longa extract is efficient on knee osteoarthritis pain: a double-blind multicenter randomized placebo controlled three-arm study. Full Text
*Food matrix and co-presence of turmeric compounds influence bioavailability of curcumin in healthy humans.
Does Turmeric/curcumin Supplementation Change Anthropometric Indices in Patients with Non-alcoholic Fatty Liver Disease? A Systematic Review and Meta-analysis of Randomized Controlled Trials Full Text
Is curcumin bioavailability a problem in humans: lessons from clinical trials.
Anti-inflammatory Action of Curcumin and Its Use in the Treatment of Lifestyle-related Diseases Full Text

Fisetin – a flavonoid found in highest concentration in strawberries. Senolytic, anti-inflammatory, anti-cancer, neuro-protective & Sirt1 activator. I take 100mg daily.
Nicotinamide MonoNucleotide (NMN) – newer NAD+ precursor. I take 250mg daily.

Nicotinamide Riboside (NR) – NAD+ precursor.
*Safety and Metabolism of Long-term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-controlled Clinical Trial of Healthy Overweight Adults Full Text
Nicotinamide riboside promotes autolysosome clearance in preventing doxorubicin-induced cardiotoxicity.

Pterostilbene – found in blueberries. Anti-oxidant, anti-inflamatory and Sir1 activator. Similar to, but with greater bioavailability than resveratrol. Just started taking 50mg again daily. Works better in conjunction with NAD+ precursors.
Pterostilbene: Mechanisms of its action as oncostatic agent in cell models and in vivo studies.
Antidiabetic effects of pterostilbene through PI3K/Akt signal pathway in high fat diet and STZ-induced diabetic rats.
Prevention of Vascular Inflammation by Pterostilbene via Trimethylamine-N-Oxide Reduction and Mechanism of Microbiota Regulation

Resveratrol – found in the skin of grapes. Anti-oxidant, anti-inflamatory and Sir1 activator. Just started taking 250mg a day. Works better in conjunction with NAD+ precursors & Spermidine.
*The Effects of Resveratrol Supplementation on Endothelial Function and Blood Pressures Among Patients with Metabolic Syndrome and Related Disorders: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
*Effect of resveratrol on non-alcoholic fatty liver disease Full Text
*Health Benefits of Resveratrol in Kidney Disease: Evidence from In Vitro and In Vivo Studies. Full Text
*Resveratrol and cognitive decline: a clinician perspective. Full Text
Resveratrol alleviates chronic "real-world" ambient particulate matter-induced lung inflammation and fibrosis by inhibiting NLRP3 inflammasome activation in mice.
Resveratrol shifts energy metabolism to increase lipid oxidation in healthy old mice. Full Text

Spermidine – found in wheat germ and a potent inducer of autophagy, it works in synergy with Resveratrol. I try to eat a couple of tablespoons of wheat germ every day.
Spermidine Confers Liver Protection by Enhancing NRF2 Signaling Through a MAP1S-Mediated Noncanonical Mechanism.
The metabolomic signature of extreme longevity: naked mole rats versus mice. Full Text
Polyamines in Food Full Text

Prescription Supplements

Rapamycin (sirolimus) – first drug proven to increase the health & lifespan of mice. Currently used for organ transplantation and against cancer. Taking 5mg once a week.
*Oral and Topical Sirolimus for Vascular Anomalies: a Multicentre Study and Review. Full Text
*Sirolimus as a new drug to treat RIF patients with elevated Th17/Treg ratio: A double-blind, phase II randomized clinical trial.
Differential effects of rapamycin on glucose metabolism in 9 inbred strains.
Targeting mTOR for cancer therapy Full Text
Partial inhibition of mTORC1 in aged rats counteracts the decline in muscle mass and reverses molecular signaling associated with sarcopenia. Full Text
mTOR as a central regulator of lifespan and aging. Full Text
A novel rapamycin analog is highly selective for mTORC1 in vivo. Full Text
Lifespan extension drug interventions affect adipose tissue inflammation in aging.
Effect of caloric restriction and rapamycin on ovarian aging in mice

Senolytics – not supplements or available now, but the most exciting area of anti-research at the moment. I intend to take the plunge into senolytics within the next year, before giving them to my parents:
Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy Full Text
Stabilizing heterochromatin by DGCR8 alleviates senescence and osteoarthritis. Full Text
Increased renal cellular senescence in murine high-fat diet: effect of the senolytic drug quercetin
Cellular Senescence and the Kidney: Potential Therapeutic Targets and Tools. Full Text

The big news from me is that I volunteered at Ending Age Related Diseases 2019 in New York on 11^th-12^th July. I got to be one of the two timekeepers and therefore got to watch all of the presentations and discussions from the front row. It was an amazing, yet exhausting experience – who knew that simply keeping track of time could be so tiring? I will mention more next month, as I want to get this update out, having originally planned to get it out before I went. I had also planned to live tweet the event but there wasn’t any time – speaking of which…

Follow me on Twitter @ChrisPollyanna1 for the latest updates!

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NOTE: I’ve been having trouble linking to the science journal hacking site sci-hub.tw, so am only including Full Text links to articles not behind a paywall. I have still been able to download most of them, so if there are any that you are after, I can send them upon request.

June Round-Up

• Senolytics are the most promising near term rejuvenatory therapeutics. If the data from mice in any way translates to humans, then their impact will be profound. Here is the second set of preliminary results in humans (the first being in January with a different drug combo). This is from a commercial company hoping to bring it to market against arthritis initially. This was a phase 1 study, so it was meant to check for any potential side effects, not how well it worked. There were no major side effects and initial indications of a dose response, which is extremely encouraging. To my surprise the longevity community didn’t do cartwheels of joy, but I think most of them didn’t dig into the results or watch the company presentation, which I have included here for the added detail:

*Unity Biotechnology Releases UBX0101 Results Unity Conference Call with Powerpoint

• Even if you were to make it to 110 years of age without suffering any of the major diseases of ageing, something will still get you in the end. That “something” turns out to be amyloidosis, the deposition of amyloid throughout the body, which was found to be the main cause of death among supercentenarians. I realise this must be keeping you awake at night! Fear not however, as the first in human trial of a drug to treat this most pressing of conditions has taken place:

*First-in-Human Study of AG10, a Novel, Oral, Specific, Selective, and Potent Transthyretin Stabilizer for the Treatment of Transthyretin Amyloidosis: A Phase 1 Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Study in Healthy Adult Volunteers. Full Text

• Urolithin A is a substance which our gut microbes can produce from a molecule found in pomegranate (ellagitannins) and which might help our mitochondria (the powerhouse of our cells). Urolithin A has been found to increase the lifespan of model organisms, however even more interestingly, the study below was done in humans and although was not aimed at improving lifespan, showed an improvement in their mitochondria. For those of you who like to go down the rabbit hole, I’ve also included a link to a video review of the paper by LEAF, who review a longevity paper every month on their Facebook page:

*Positive Results from Urolithin A Human Trial LEAF Journal Club June edition on Urolithin A paper

• Here is another study showing that a means of increasing NAD+ in the body (of mice) could increase lifespan by around 16%, this time using a protein, eNAMPT, which declines with age. This is hopeful for those of us who take NAD+ precursors such as Nicotinamide Mononucleuotide (NMN) or Nicotinamide Riboside (NR).

NAMPT Delays Aging and Extends Lifespan in Mice

• I’ve mentioned many times before about the potential benefits of transferring young blood or plasma to older individuals. Here is a rather different proposition entirely! It turns out that the composition of our gut microbes changes with age, and by transplanting the gut microbes of a young mouse to an old one improves one aspect of ageing:

Transplanting Gut Microbes from Young to Old Mice Reverses Immune Decline Full Text

• The thymus is a vital organ of our immune system which unfortunately shrinks with age. If the thymus could be rejuvenated, out immune system would improve and reduce the incidence of life threatening infections, which are significant source of mortality for the elderly. Here, scientists have made progress in engineering a man made replacement for the thymus’s decline:

Creating Thymus Organoids Using Tissue Engineering Full Text

Research Institutes:
SENS Research Foundation (I have a recurring monthly donation)
Buck Institute

Private initiatives:
Age-Reversal Network (good information & forums for those interested in self-experimentation – this is where I found how to get non-prescription Rapamycin)
Better Humans
Gerontology Research Group
Lifespan.io (Tied together with LEAF, I have a recurring monthly donation)

======================================================================================================================

June Supplemental Information

***Disclaimer 1 – As should be self-evident to anyone receiving these emails, I am NOT a doctor or indeed a scientist. All the information pertained within is for information purposes only; use at your own risk. Please consult with a healthcare practitioner if needing medical advice.***

**Disclaimer 2 – In no way should supplements be a replacement for an unhealthy diet or lifestyle. A varied, plant dominant dietary pattern is the cornerstone for health. Try to eat the rainbow – the greater the variety, the greater the benefit. Even though I might take a supplement derived from a plant source, I still eat the plant in question. Also, make sure you move as much as possible – that is what we evolved to do.**

*Also bear in mind that most of the studies mentioned below are in rodents, not humans. Rodents, needless to say, do not always react the same way to drugs as humans do – witness the countless times cancer or another disease has been cured in rodents only to subsequently fail human trials. I have *bolded any human trials.*
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Lifestyle

Fasting/Dietary Restriction – certainly the cheapest & also one of the most effective anti-ageing interventions currently available. It comes in many flavours, but I fast for at least 12 hours every day.

*The Effects of Time Restricted Feeding on Overweight, Older Adults: A Pilot Study Full Text
Time-restricted feeding delays the emergence of the age-associated, neoplastic-prone tissue landscape. Full Text
Time-restricted feeding restores muscle function in Drosophila models of obesity and circadian-rhythm disruption Full Text
Dietary restriction induces posttranscriptional regulation of longevity genes. Full Text

Diet – let food be thy medicine…

*Positive Associations of Dietary Marine Omega-3 Polyunsaturated Fatty Acids with Lung Function: A Meta-analysis Full Text
*Strawberry Consumption Associated with Reduced Alzheimer's Dementia Risk Full Text
*Garlic Consumption and All-Cause Mortality among Chinese Oldest-Old Individuals: A Population-Based Cohort Study. Full Text
Habitual tea drinking modulates brain efficiency: evidence from brain connectivity evaluation. Full Text
Lycopene inhibits smoke-induced chronic obstructive pulmonary disease and lung carcinogenesis by modulating reverse cholesterol transport in ferrets.
Protective effect of green tea catechin against urban fine dust particle-induced skin aging by regulation of NF-κB, AP-1, and MAPKs signaling pathways

Exercise – if you could bottle the benefits of exercise, it would be the biggest blockbuster drug of all time.

*Resistance Exercise Training as a Primary Countermeasure to Age-Related Chronic Disease Full Text
*Strength training and protein supplementation improve muscle mass, strength, and function in mobility-limited older adults: a randomized controlled trial.
*Exercise Reverses Age‐Related Decline in NAD+ Salvage Capacity Full Text

Non-prescription Supplements (in alphabetical order)

Astaxanthin – which is behind the pink colour of salmon & shrimp. Considered the most powerful carotinoid, it has anti-oxidative, anti-inflamatory, anti-cancer, neuro-protective and skin-protective qualities. I take 4mg daily.

Astaxanthin Inhibits Alcohol-induced Inflammation and Oxidative Stress in Macrophages Full Text
Astaxanthin protects against renal fibrosis through inhibiting myofibroblast activation and promoting CD8+ T cell recruitment.

Curcumin – the spice which gives curries their yellow colour. Anti-inflammatory and neuroprotective. I take 1 gram a day. Needs to be taken with black pepper (piperine) to improve bio-availability.

*Curcuminoids plus piperine improve nonalcoholic fatty liver disease: A clinical trial.
*Effects of curcumin supplementation on markers of inflammation and oxidative stress among healthy overweight and obese girl adolescents: A randomized placebo-controlled clinical trial.
*Evaluation of the efficacy and safety of Capsule Longvida® Optimized Curcumin (solid lipid curcumin particles) in knee osteoarthritis: a pilot clinical study. Full Text
*A Highly Bioavailable Curcumin Extract Improves Neurocognitive Function and Mood in Healthy Older People: A 12-Week Randomised, Double-Blind, Placebo-Controlled Trial Full Text
Benefits of curcumin in brain disorders.

Fisetin – a flavonoid found in highest concentration in strawberries. Senolytic, anti-inflammatory, anti-cancer, neuro-protective & Sirt1 activator. I take 100mg daily.

Phytomedicine-Based Potent Antioxidant, Fisetin Protects CNS-Insult LPS-Induced Oxidative Stress-Mediated Neurodegeneration and Memory Impairment. Full Text
Induction of endothelial dysfunction by oxidized low-density lipoproteins via downregulation of Erk-5/Mef2c/KLF2 signaling: Amelioration by Fisetin.

Nicotinamide MonoNucleotide (NMN) – newer NAD+ precursor. I take 250mg daily.

Nicotinamide phosphoribosyltransferase postpones rat bone marrow mesenchymal stem cell senescence by mediating NAD+-Sirt1 signaling. Full Text

Nicotinamide Riboside (NR) – NAD+ precursor.

Role of mitochondria in diabetic peripheral neuropathy: Influencing the NAD+-dependent SIRT1-PGC-1α-TFAM pathway. Full Text
Nicotinamide Riboside, an NAD + Precursor, Reduces Hepatic Stellate Cell Activation and Attenuates Liver Fibrosis in a Diet-induced Mouse Model of Liver Fibrosis Full Text

Pterostilbene – found in blueberries. Anti-oxidant, anti-inflamatory and Sir1 activator. Similar to, but with greater bioavailability than resveratrol. Just started taking 50mg again daily. Works better in conjunction with NAD+ precursors.

Stilbene Compounds Inhibit Tumor Growth by the Induction of Cellular Senescence and the Inhibition of Telomerase Activity. Full Text
Pterostilbene reverses palmitic acid mediated insulin resistance in HepG2 cells by reducing oxidative stress and triglyceride accumulation.

Resveratrol – found in the skin of grapes. Anti-oxidant, anti-inflamatory and Sir1 activator. Just started taking 250mg a day. Works better in conjunction with NAD+ precursors & Spermidine.

The impact of resveratrol on toxicity and related complications of advanced glycation end products: A systematic review.
*Higher Dietary Intake of Resveratrol Was Associated with Lower Risk of Hip Fracture- a 1:1 Matched Case-control Study in Chinese Elderly Full Text

Spermidine – found in wheat germ and a potent inducer of autophagy, it works in synergy with Resveratrol. I try to eat a couple of tablespoons of wheat germ every day.

Prescription Supplements

Rapamycin (sirolimus) – first drug proven to increase the health & lifespan of mice. Currently used for organ transplantation and against cancer. Taking 5mg once a week.

Stimulation of Hair Growth by Small Molecules that Activate Autophagy Full Text
Effect of sirolimus on coagulopathy of slow-flow vascular malformations
The impact of sirolimus therapy on lesion size, clinical symptoms, and quality of life of patients with lymphatic anomalies Full Text
Protective effects of rapamycin induced autophagy on CLP septic mice.
Rapamycin Affects Palmitate-Induced Lipotoxicity in Osteoblasts by Modulating Apoptosis and Autophagy.
mTOR and Aging: An Old Fashioned Dress (Rapamycin Review) Full Text
Deregulated MTOR (mechanistic target of rapamycin kinase) is responsible for autophagy defects exacerbating kidney stone development.
Longevity-related molecular pathways are subject to midlife "switch" in humans. Full Text

Senolytics – not supplements or available now, but the most exciting area of anti-research at the moment. I intend to take the plunge into senolytics within the next year, before giving them to my parents:

Cellular senescence in cardiac diseases. Full Text
Knockdown of angiopoietin-like 2 induces clearance of vascular endothelial senescent cells by apoptosis, promotes endothelial repair and slows atherogenesis in mice. Full Text
Slug Saves Satellite Cells from Senescence Full Text
NAD+ and Cellular Senescence Pathways Interact
Directed elimination of senescent cells attenuates development of osteoarthritis by inhibition of c-IAP and XIAP.

Follow me on Twitter @ChrisPollyanna1 for the latest updates.

Finally – please feel free to forward this email to anyone who might be interested, and please let me know if anyone would like to be included in my mailing list!
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NOTE: I’ve been having trouble linking to the science journal hacking site sci-hub.tw, so am only including Full Text links to articles not behind a paywall. I have still been able to download most of them, so if there are any that you are after, I can send them upon request.

May Round-Up

• One line of attack against ageing not touched upon this year yet is the restoration of our telomeres, the protective caps at the end of our chromosomes which shorten with age. Previous studies have suggested health improvements with their elongation. The present study by the leader in the field continues this trend, this time looking at mental function:

• Another month, another factor found in blood, VCAM1, which increases with age and whose removal shows beneficial effects. Once again this is in relation to the brain:

• Unlike the study above, which looked at old blood, the one below looks at the beneficial effects of young plasma derived from blood, also in the brain, but this time after injury:

• A rather exciting study for me about my favourite anti-ageing drug Rapamycin, which shows that it slows down an epigenetic ageing clock - yet more proof that it affects one of the main ageing pathways. However the authors do explicitly warn not to extrapolate the results to humans – I’ve conveniently decided to ignore that!

• Yet another method to find anti-ageing drugs amongst existing approved drugs is unveiled here. Similar to last month, they discovered four drugs which extended worm lifespan by up to 30%. Interestingly lower doses were better than higher, which proved to be toxic. Unfortunately, they didn’t combine them with other drugs to see if there would be any synergistic effects.

• Cells have various methods to communicate with one another, one of which is the use of exosomes, small packets of proteins and other molecules which provide signaling information. It was recently found that that certain ones from younger animals can have anti-ageing effects. These two studies are further examples of that.

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Videos to watch

The Buck Institute in California was the first institution devoted solely to the study of ageing when it opened its doors in 1999. It remains one of the premier institutes of its kind. This year, as part of celebrations to mark the 30th anniversary of the paper which kicked off the modern study of ageing, they launched a Webinar series, where they interviewed some of the leading lights of the field. Those watching live could also ask questions. Happily, all my questions were answered! The interviews with Judith Campisi and Steve Austad in particular are worth a watch:
https://buck.extendedsession.com/

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Further sources of information:
Fight Aging!
Life Extension Advocacy Foundation (LEAF)
Longecity (good forums where the self-experimenters reside!)
Research Institutes:
SENS Research Foundation (I have a recurring monthly donation)
Buck Institute
Private initiatives:
Age-Reversal Network (good information & forums for those interested in self-experimentation – this is where I found how to get non-prescription Rapamycin)
Better Humans
Gerontology Research Group
Lifespan.io (Tied together with LEAF, I have a recurring monthly donation)

======================================================================================================================

May Supplemental Information

***Disclaimer 1 – As should be self-evident to anyone receiving these emails, I am NOT a doctor or indeed a scientist. All the information pertained within is for information purposes only; use at your own risk. Please consult with a healthcare practitioner if needing medical advice.***

**Disclaimer 2 – In no way should supplements be a replacement for an unhealthy diet or lifestyle. A varied, plant dominant dietary pattern is the cornerstone for health. Try to eat the rainbow – the greater the variety, the greater the benefit. Even though I might take a supplement derived from a plant source, I still eat the plant in question. Also, make sure you move as much as possible – that is what we evolved to do.**

*Also bear in mind that most of the studies mentioned below are in rodents, not humans. Rodents, needless to say, do not always react the same way to drugs as humans do – witness the countless times cancer or another disease has been cured in rodents only to subsequently fail human trials. I have *bolded any human trials.*
------------------------------------------------------------------------------------------------------------------------------

Lifestyle

Fasting/Dietary Restriction – certainly the cheapest & also one of the most effective anti-ageing interventions currently available. It comes in many flavours, but I fast for at least 12 hours every day.

*Early Time-Restricted Feeding Improves 24-Hour Glucose Levels and Affects Markers of the Circadian Clock, Aging, and Autophagy in Humans. Full text

Diet – let food be thy medicine…

*Eating blueberries every day improves heart health Full Text
*Coffee consumption and all-cause and cause-specific mortality: a meta-analysis by potential modifiers.
*High flavonoid cocoa supplement ameliorates plasma oxidative stress and inflammation levels while improving mobility and quality of life in older subjects: a double blind randomized clinical trial.
*The Efficacy of Cocoa Polyphenols in the Treatment of Mild Cognitive Impairment: A Retrospective Study Full Text
*The Association between Green and Black Tea Consumption on Successful Aging: A Combined Analysis of the ATTICA and MEDiterranean ISlands (MEDIS) Epidemiological Studies. Full text

Exercise – if you could bottle the benefits of exercise, it would be the biggest blockbuster drug of all time.

*Similar Effects of 24 Weeks of Resistance Training Performed with Different Frequencies on Muscle Strength, Muscle Mass, and Muscle Quality in Older Women. Full Text

Non-prescription Supplements (in alphabetical order)

Astaxanthin – which is behind the pink colour of salmon & shrimp. Considered the most powerful carotinoid, it has anti-oxidative, anti-inflamatory, anti-cancer, neuro-protective and skin-protective qualities. I take 4mg daily.

Astaxanthin exerts protective effects similar to bexarotene in Alzheimer's disease by modulating amyloid beta and cholesterol homeostasis in blood-brain barrier endothelial cells.
Leptin in hippocampus mediates benefits of mild exercise by an antioxidant on neurogenesis and memory.
Comparison of Carotenoids for Their Antifibrogenic Effects in Hepatic Stellate Cells.
Protective effects of astaxanthin on skin: Recent scientific evidence, possible mechanisms, and potential indications.
Heamatococcus pluvialis ameliorates bone loss in experimentally-induced osteoporosis in rats via the regulation of OPG/RANKL pathway.

Curcumin – the spice which gives curries their yellow colour. Anti-inflammatory and neuroprotective. I take 1 gram a day. Needs to be taken with black pepper (piperine) to improve bio-availability.

*Curcumin in Autoimmune and Rheumatic Diseases. Full Text
*The effect of curcumin supplementation on anthropometric indices, insulin resistance and oxidative stress in patients with type 2 diabetes: a randomized, double-blind clinical trial. Full Text
*The effect of curcumin with piperine supplementation on pro-oxidant and antioxidant balance in patients with non-alcoholic fatty liver disease: a randomized, double-blind, placebo-controlled trial.
*Oral turmeric/curcumin effects on inflammatory markers in chronic inflammatory diseases: A systematic review and meta-analysis of randomized controlled trials.
Chemopreventive efficacy of oral curcumin: a prodrug hypothesis.
Natural Dietary Supplementation of Curcumin Protects Mice Brains against Ethanol-Induced Oxidative Stress-Mediated Neurodegeneration and Memory Impairment via Nrf2/TLR4/RAGE Signaling. Full Text

Fisetin – a flavonoid found in highest concentration in strawberries. Senolytic, anti-inflammatory, anti-cancer, neuro-protective & Sirt1 activator. I take 100mg daily.

Fisetin and Quercetin: Promising Flavonoids with Chemopreventive Potential. Full Text
Fisetin supplementation prevents high fat diet-induced diabetic nephropathy by repressing insulin resistance and RIP3-regulated inflammation.
Endoplasmic reticulum stress-induced iRhom2 up-regulation promotes macrophage-regulated cardiac inflammation and lipid deposition in high fat diet (HFD)-challenged mice.

Nicotinamide MonoNucleotide (NMN) – newer NAD+ precursor. I take 250mg daily.

Implications of altered NAD metabolism in metabolic disorders. Full Text
Nicotinamide mononucleotide (NMN) treatment attenuates oxidative stress and rescues angiogenic capacity in aged cerebromicrovascular endothelial cells: a potential mechanism for the prevention of vascular cognitive impairment.
Sirt1 counteracts decrease in membrane phospholipid unsaturation and diastolic dysfunction during saturated fatty acid overload.

Nicotinamide Riboside (NR) – NAD+ precursor.

PGC-1α, Sirtuins and PARPs in Huntington's Disease and Other Neurodegenerative Conditions: NAD+ to Rule Them All.

Pterostilbene – found in blueberries. Anti-oxidant, anti-inflamatory and Sir1 activator. Similar to, but with greater bioavailability than resveratrol. Just started taking 50mg again daily. Works better in conjunction with NAD+ precursors.

Pterostilbene Ameliorates Nephropathy Injury in Streptozotocin-Induced Diabetic Rats.
Pterostilbene Activates the Nrf2-Dependent Antioxidant Response to Ameliorate Arsenic-Induced Intracellular Damage and Apoptosis in Human Keratinocytes. Full Text

Resveratrol – found in the skin of grapes. Anti-oxidant, anti-inflamatory and Sir1 activator. Just started taking 250mg a day. Works better in conjunction
with NAD+ precursors & Spermidine.

Grape Peel Extract and Resveratrol Inhibit Wrinkle Formation in Mice Model Through Activation of Nrf2/HO-1 Signaling Pathway.
Effects of resveratrol supplementation in male Wistar rats undergoing an endurance exercise and acute exercise training.
Effect of resveratrol on metabolic syndrome components: A systematic review and meta-analysis.
The Effects of Dietary Supplements That Overactivate the Nrf2/ARE System.
Exploration of age-related mitochondrial dysfunction and the anti-aging effects of resveratrol in zebrafish retina. Full Text

Spermidine – found in wheat germ and a potent inducer of autophagy, it works in synergy with Resveratrol. I try to eat a couple of tablespoons of wheat germ every day.

*Endothelial Function is improved by Inducing Microbial Polyamine Production in the Gut: A Randomized Placebo-Controlled Trial. Full Text
Spermidine-enhanced autophagic flux improves cardiac dysfunction following myocardial infarction by targeting AMPK/mTOR signaling pathway.

Prescription Supplements

Rapamycin – first drug proven to increase the health & lifespan of mice. Currently used for organ transplantation and against cancer. Have taken four doses of 2.5mg, four at 3.75mg and will be moving to 5mg once my surgical wounds have closed up (it delays wound healing). The last two articles here actually show some potential negative side effects – something I’m not going to shy away from disclosing to you!

Rapamycin attenuates articular cartilage degeneration by inhibiting β-catenin in a murine model of osteoarthritis.
Rapamycin modulates tissue aging and lifespan independently of the gut microbiota in Drosophila Full Text
Rapamycin and Alzheimer disease: a double-edged sword?
Inhibition of mTOR by Rapamycin Aggravates Corneal Epithelial Stem Cell Deficiency by Upregulating Inflammatory Response.
Alteration of the Wnt/GSK3β/β catenin signalling pathway by rapamycin ameliorates pathology in an Alzheimer's disease model.
Mammalian Target of Rapamycin: Is It Relevant to COPD Pathogenesis or Treatment?
Do drugs that target mTOR generate CCN2-mediated fibrogenic side effects?

Senolytics – not supplements or available now, but the most exciting area of anti-research at the moment. I intend to take the plunge into senolytics within the next year, before giving them to my parents:

Senescent Cells and Cataract Development Full Text
Regulation of Survival Networks in Senescent Cells: From Mechanisms to Interventions. Full text
Senescent cell clearance by the immune system: Emerging therapeutic opportunities.
Acceleration of β Cell Aging Determines Diabetes and Senolysis Improves Disease Outcomes
Restored immune cell functions upon clearance of senescence in the irradiated splenic environment
Interacting NAD+ and Cell Senescence pathways complicate anti-aging therapies.

On a personal level, I took a hiatus from my self-experiment whilst I recovered from my second hand operation, but have now resumed. There’s still nothing to report there, but my parents have finally received their own supply of Rapamycin, so it will be interesting to see if it has any positive effect on them. I joined another longevity organization – the Gerontology Research Group, which, as it has many scientists as members, should provide another source of good information. Also, I’m beginning, at long last, to post more regularly on twitter – follow me @ChrisPollyanna1 for the latest updates.

Finally – please feel free to forward this email to anyone who might be interested, and please let me know if anyone would like to be included in my mailing list!
-------------------------------------------------------------------------------------------------------------------------------------
NOTE: I’ve been having trouble linking to the science journal hacking site sci-hub.tw, so am only including Full Text links to articles not behind a paywall. I have still been able to download most of them, so if there are any that you are after, I can send them upon request.

April Round-Up

• Advanced Glycation End Products (AGEs) are compounds which are formed when fats & proteins combine with sugars (either during cooking or inside our bodies) to cause problems, such as the stiffening of arteries or wrinkles in the skin, as they accumulate with time. So far, there had been no way to get rid of them once they have formed, however, the study below marks the first time that this has been achieved. Although early days, these are important first steps:

• I’ve talked about in the past about how the replenishment of some factors in blood, which decline with age, might reverse some aspects of ageing (eg GDF11). Conversely, there are factors in blood which increase with age, and their removal might likewise help with ageing. The study below blocked a different protein (CD22) which increases with age, and whose blockage reversed cognitive decline in mice:

• Stem cells, one way or another, are going to be needed in this fight against ageing, however, up until now there has been little definitive proof that the current technology is effective, despite the proliferation of stem cell clinics. Therefore, it is nice to see in the trial below that stem cells are somewhat effective in treating knee osteoarthritis:

• To show what might be eventually possible with stem cells, the study below increased the maximum lifespan of mice by 28% with the transplantation of bone marrow from young to aged animals. This echoes a human study I reported on last year which improved markers of frailty with a transfusion of stem cells:

• One problem with transplanting stem cells is that stem cells themselves age, which is why in the study above, bone marrow was taken from young animals. But what if the old stem cells could be rejuvenated like the silver bullet of cellular re-programming, which I gushed on about last month? Well, how about the study below then, which did precisely that!

• Fortunately, there is a continued push by scientists to find new molecules which might combat ageing. Here is another example of a new class of drugs (Hsp90 inhibitors) being found which extend the lifespan of worms. What makes this study more exciting is not that they found some potential life-extending molecules, but that they further tested them in combination with proven life-extending molecules such as Rapamycin (yeah!) and found that there was a synergistic effect – further increasing the worms lifespans:

• Finally, for something more applicable in the near term, the following study showed how the low dose combination of a Statin and Angiotensin II Receptor Blocker (for blood pressure) can increase the expression of pro-longevity genes in humans:

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In March an anti-ageing conference took place in Berlin (Undoing Aging 2019) which was notable for the level of optimism amongst the attendees. The conference featured much of the who’s who in the ageing research field. All the presentations were recorded and they have now started to be posted onto YouTube. As of this writing only three have been posted, but more will undoubtedly follow. The talks from the previous year’s conference are also available on the page:

https://www.youtube.com/channel/UCAwxbQhlE6qcTXmKcxkaCGA

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Further sources of information:
Fight Aging!
Life Extension Advocacy Foundation (LEAF)
Longecity (good forums where the crazy self-experimenters reside!)
Research Institutes:
SENS Research Foundation (I have a recurring monthly donation)
Buck Institute
Private initiatives:
Age-Reversal Network (good information & forums for those interested in self-experimentation – this is where I found how to get non-prescription Rapamycin)
Better Humans
Gerontology Research Group
Lifespan.io (Tied together with LEAF, I have a recurring monthly donation)

======================================================================================================================

Supplemental Information

***Disclaimer 1 – As should be self-evident to anyone receiving these emails, I am NOT a doctor or indeed a scientist. All the information pertained within is for information purposes only; use at your own risk. Please consult with a healthcare practitioner if needing medical advice.***

**Disclaimer 2 – In no way should supplements be a replacement for an unhealthy diet or lifestyle. A varied, plant dominant dietary pattern is the cornerstone for health. Try to eat the rainbow – the greater the variety, the greater the benefit. Even though I might take a supplement derived from a plant source, I still eat the plant in question. Also, make sure you move as much as possible – that is what we evolved to do.**

*Also bear in mind that most of the studies mentioned below are in rodents, not humans. Rodents, needless to say, do not always react the same way to drugs as humans do – witness the countless times cancer or another disease has been cured in rodents only to subsequently fail human trials. I have *bolded any human trials.*
------------------------------------------------------------------------------------------------------------------------------

Lifestyle

Fasting/Dietary Restriction – certainly the cheapest & also one of the most effective anti-ageing interventions currently available. It comes in many flavours, but I fast for at least 12 hours every day.

*After heart attack: Late dinner and no breakfast a killer combination Full Text
The Impact of Caloric Restriction on the Epigenetic Signatures of Aging. Full Text
Meal Timing, Aging, and Metabolic Health. Full Text

Diet – let food be thy medicine…

Longevity and cause of death in male Wistar rats fed lifelong diets based on virgin olive oil, sunflower oil or fish oil.
*Diet rich in animal protein is associated with a greater risk of early death

Exercise – if you could bottle the benefits of exercise, it would be the biggest blockbuster drug of all time.

*Aerobic Exercise Improves Microvascular Function in Older Adults.
*Effects of high-velocity resistance training and creatine supplementation in untrained healthy aging males.

Non-prescription Supplements (in alphabetical order)

Astaxanthin – which is behind the pink colour of salmon & shrimp. Considered the most powerful carotinoid, it has anti-oxidative, anti-inflamatory, anti-cancer, neuro-protective and skin-protective qualities. I take 4mg daily.

Effects of astaxanthin on sensory-motor function in a compression model of spinal cord injury: Involvement of ERK and AKT signalling pathway. Full Text
Effects of Astaxanthin Supplementation on Oxidative Stress.
Astaxanthin as a Peroxisome Proliferator-Activated Receptor (PPAR) Modulator: Its Therapeutic Implications. Full Text

Curcumin – the spice which gives curries their yellow colour. Anti-inflammatory and neuroprotective. I take 1 gram a day. Needs to be taken with black pepper (piperine) to improve bio-availability.

*Metabolic benefits of curcumin supplementation in patients with metabolic syndrome: A systematic review and meta-analysis of randomized controlled trials.
*Safety and efficacy of curcumin versus diclofenac in knee osteoarthritis: a randomized open-label parallel-arm study. Full Text
*Curcuma longa L. ameliorates asthma control in children and adolescents: A randomized, double-blind, controlled trial.
*Effects of curcumin on glycemic control and lipid profile in prediabetes and type 2 diabetes mellitus: A systematic review and meta-analysis. Full Text
*Effect of Curcumin Supplementation on Exercise-Induced Oxidative Stress, Inflammation, Muscle Damage, and Muscle Soreness.

Fisetin – a flavonoid found in highest concentration in strawberries. Senolytic, anti-inflammatory, anti-cancer, neuro-protective & Sirt1 activator. I take 100mg daily.

Fisetin and telmisartan each alone or in low-dose combination alleviate OVA-induced food allergy in mice.
Protective effect of Fisetin against angiotensin II-induced apoptosis by activation of IGF-IR-PI3K-Akt signaling in H9c2 cells and spontaneous hypertension rats.

Nicotinamide MonoNucleotide (NMN) – newer NAD+ precursor. I take 250mg daily.

Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice. Full Text
Nicotinamide mononucleotide promotes osteogenesis and reduces adipogenesis by regulating mesenchymal stromal cells via the SIRT1 pathway in aged bone marrow. Full Text

Nicotinamide Riboside (NR) – NAD+ precursor.

Cardioprotective Effect of the Mitochondrial Unfolded Protein Response During Chronic Pressure Overload. Full Text

Pterostilbene – found in blueberries. Anti-oxidant, anti-inflamatory and Sir1 activator. Similar to, but with greater bioavailability than resveratrol. Just started taking 50mg again daily. Works better in conjunction with NAD+ precursors.

Pterostilbene Reduces Liver Steatosis and Modifies Hepatic Fatty Acid Profile in Obese Rats. Full Text

Resveratrol – found in the skin of grapes. Anti-oxidant, anti-inflamatory and Sir1 activator. Just started taking 250mg a day. Works better in conjunction with NAD+ precursors & Spermidine.

Can Resveratrol Treatment Control the Progression of Induced Periodontal Disease? A Systematic Review and Meta-Analysis of Preclinical Studies. Full Text
The roles of sirtuin 1 and its activator, resveratrol in osteoarthritis. Full Text
Preventive role of Resveratrol against inflammatory cytokines and related diseases

Spermidine – found in wheat germ and a potent inducer of autophagy, it works in synergy with Resveratrol. I try to eat a couple of tablespoons of wheat germ every day.

Spermine and gene methylation: a mechanism of lifespan extension induced by polyamine-rich diet.

Prescription Supplements

Rapamycin – first drug proven to increase the health & lifespan of mice. Currently used for organ transplantation and against cancer. Have taken four doses of 2.5mg, four at 3.75mg and will be moving to 5mg once my surgical wounds have closed up (it delays wound healing).

Neuroprotective effects of rapamycin on spinal cord injury in rats by increasing autophagy and Akt signaling. Full Text
Alzheimer’s - Rapamycin regulates cholesterol biosynthesis and cytoplasmic ribosomal proteins in hippocampus and temporal lobe of APP/PS1 mouse.
Osteoarthritis - Rapamycin Inhibits Nf-ΚB Activation by Autophagy to Reduce Catabolism in Human Chondrocytes.
Progeria -Presence and distribution of progerin in HGPS cells is ameliorated by drugs that impact on the mevalonate and mTOR pathways.
Rapamycin relieves inflammation of experimental autoimmune encephalomyelitis by altering the balance of Treg/Th17 in a mouse model.
Inhibition of mTORC1 signaling in aged rats counteracts the decline in muscle mass and reverses multiple parameters of muscle signaling associated with sarcopenia Full Text
Interesting paper on how Rapamycin induces reversible infertility in men – which could either be a good or bad thing!
Molecular Mechanisms Controlled by mTOR in Male Reproductive System. Full Text

Senolytics – not supplements or available now, but the most exciting area of anti-research at the moment. I intend to take the plunge into senolytics within the next year, before giving them to my parents:

Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer's disease model.
Senescence cell-associated extracellular vesicles serve as osteoarthritis disease and therapeutic markers. Full Text
Targeting Cell Senescence for the Treatment of Age-Related Bone Loss.

In 2016 a landmark paper came out showing that it was possible to rejuvenate (to a degree) an entire animal by making all of its individual cells young again by re-programming their epigenome (Cellular reprogramming slows aging in mice Full Text). Science takes time, and since then I’ve been eagerly awaiting the follow-up studies.

Those studies are now starting to arrive as shown by the one below. Although it was only performed in human cells, it shows an improvement in technique compared to the study above.

Transient non-integrative nuclear reprogramming promotes multifaceted reversal of aging in human cells

And here is an interesting interview with a member of the above team: https://www.leafscience.org/an-interview-with-prof-vittorio-sebastiano-of-turn-bio/

Here is another interview with a different company working in this area, demonstrating the breadth of this field: https://www.leafscience.org/an-interview-with-yuri-deigin/

For a more general overview of this field, this article, by the same scientist featured in last month’s podcasts, is worth a read through:
LEAF overview: Epigenetic Alterations and Reprogramming Potential in AgingAbstract: Epigenetic changes during aging and their reprogramming potential. Full Text

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March Round-Up

In a similar vein to re-programming, this study shows a different method to get heart cells to behave younger so that they grow in number (heart cells don’t generally divide that much), which could be beneficial after heart attacks for example.
YAP Partially Reprograms Chromatin Accessibility to Directly Induce Adult Cardiogenesis In Vivo. Full Text

This study used gene editing to enhance a single gene (FOXO3) so that it improves the ability of stem cells to produce new blood vessels and to prevent them from turning cancerous.
FOXO3-Engineered Human ESC-Derived Vascular Cells Promote Vascular Protection and Regeneration. Full Text

In the January update I mentioned that Acarbose lengthened mouse lifespan as part of the NIA’s Interventions Testing Program. Normally there is quite a gap in releases, so I was quite surprised to see another one sneak in at the end of March. This time they found out that Glycine, but unfortunately not Aspirin or Inulin, extends the lifespan of mice by 4 to 6%.
Glycine supplementation extends lifespan of male and female mice

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In this month’s video/pod-cast, I want to draw your attention to a 20 minute presentation given by Jim Mellon, who is a very well respected billionaire investor. In the last few years he’s jumped into anti-ageing big time, investing millions into companies while at the same time claiming that this field will turn into the biggest “money fountain” the world has ever seen. He knows what he’s talking about as evidenced by his book Juvenescence, and in his talk he gives a whirlwind tour through the state of the field and why he is so optimistic. His enthusiasm is infectious! (PS – in the talk he also says that he is going to start taking Rapamycin after witnessing the effects it’s had on his dog!)
Jim Mellon – Abundance 360 Presentation:

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On a personal level, I’ve now upped my weekly Rapamycin dose to 3.75mg, which I will do four times before going to 5mg. So far I’ve not noticed anything apart from maybe making it easier to lose the bit of weight I was trying to. The important thing is no discernable side effects. My big news is that I’ve been granted the chance to volunteer at an anti-ageing conference in New York in July. I’m super excited about this, as it will allow me to meet some of the luminaries of the field and hear about the latest breakthroughs.

In the supplemental attachment, I’ve expanded the lifestyle and senolytic sections. I realise that it is probably a bit overwhelming at the moment, and I will try to improve that in future updates, but it is primarily to be used as a reference source if you want to dive deep into the rabbit hole. For those of you that do, the highlights include human trials with Curcumin & Resveratrol as well as a plethora of Rapamycin studies ranging from why it improves the quality of protein production to why it might prevent both Cancer & Alzheimer’s (making me feel all the better for taking it myself) and a gaggle of senescent cell studies showing just how important their removal will turn out to be for reversing ageing.

Finally – please feel free to forward this email to anyone who might be interested, and please let me know if anyone would like to be included in my mailing list!

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Further sources of information:
Fight Aging!
Life Extension Advocacy Foundation (LEAF)
Longecity (good forums where the self-experimenters reside!)
Research Institutes:
SENS Research Foundation (I have a recurring monthly donation)
Buck Institute
Private initiatives:
Age-Reversal Network (good information & forums for those interested in self-experimentation – this is where I found how to get non-prescription Rapamycin)
Better Humans
Lifespan.io (Tied together with LEAF, I have a recurring monthly donation)

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Supplemental Information

***Disclaimer 1 – As should be self-evident to anyone receiving these emails, I am NOT a doctor or indeed a scientist. All the information pertained within is for information purposes only; use at your own risk. Please consult with a healthcare practitioner if needing medical advice.***

**Disclaimer 2 – In no way should supplements be a replacement for an unhealthy diet or lifestyle. A varied, plant dominant dietary pattern is the cornerstone for health. Try to eat the rainbow – the greater the variety, the greater the benefit. Even though I might take a supplement derived from a plant source, I still eat the plant in question. Also, make sure you move as much as possible – that is what we evolved to do.**

*Also bear in mind that most of the studies mentioned below are in rodents, not humans. Rodents, needless to say, do not always react the same way to drugs as humans do – witness the countless times cancer or another disease has been cured in rodents only to subsequently fail human trials. I have *bolded any human trials.*
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Lifestyle

Fasting/Dietary Restriction – certainly the cheapest & also one of the most effective anti-ageing interventions currently available. It comes in many flavours, but I fast for at least 12 hours every day.

The Influence of Meal Frequency and Timing on Health in Humans: The Role of Fasting. Full Text
Dietary Restriction Extends Lifespan through Metabolic Regulation of Innate Immunity. Full Text
Dietary Restrictions and Nutrition in the Prevention and Treatment of Cardiovascular Disease. Full Text

Diet – let food be thy medicine…

Mediterranean-Style Diet Improves Systolic Blood Pressure and Arterial Stiffness in Older Adults. Full Text
Increased Consumption of Virgin Olive Oil, Nuts, Legumes, Whole Grains, and Fish Promotes HDL Functions in Humans. Full Text
Essential oils and functional herbs for healthy aging. Full Text

Exercise – if you could bottle the benefits of exercise, it would be the biggest blockbuster drug of all time.

Ten years younger: Practice of chronic aerobic exercise improves attention and spatial memory functions in ageing. Full Text
Physical Activity Alleviates Cognitive Dysfunction of Alzheimer's Disease through Regulating the mTOR Signaling Pathway. Full Text
Which type of exercise keeps you young? Full Text

Non-prescription Supplements (in alphabetical order)

Astaxanthin – which is behind the pink colour of salmon & shrimp. Considered the most powerful carotinoid, it has anti-oxidative, anti-inflamatory, neuro-protective and skin-protective qualities. I take 4mg daily.
The first study shows how Astaxanthin can be used to keep your skin youthful, though I’ve not really noticed anything yet myself with four months usage.

Astaxanthin has Distinct Biological Effects to Prevent the Photoaging of the Skin Even by its Postirradiation Treatment. Full text
Astaxanthin ameliorates cardiomyocyte apoptosis after coronary microembolization by inhibiting oxidative stress via Nrf2/HO-1 pathway in rats.
Effects of palmitate and astaxanthin on cell viability and proinflammatory characteristics of mesenchymal stem cells. Full Text

Curcumin – the spice which gives curries their yellow colour. Anti-inflammatory and neuroprotective. I take 1 gram a day. Needs to be taken with black pepper (piperine) to improve bio-availability.

*The effects of Curcumin supplementation on high-sensitivity C-reactive protein, serum adiponectin, and lipid profile in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled trial. Full Text
*Pharmacokinetics, Pharmacodynamics, and PKPD Modeling of Curcumin in Regulating Antioxidant and Epigenetic Gene Expression in Healthy Human Volunteers. Full Text
*The effects of Curcumin supplementation on liver enzymes, lipid profile, glucose homeostasis, and hepatic steatosis and fibrosis in patients with non-alcoholic fatty liver disease. Full Text
Curcumin intervention for cognitive function in different types of people: A systematic review and meta-analysis.
The Role of Curcumin in the Modulation of Ageing. Full Text
Nutrition and Wound Healing: An Overview Focusing on the Beneficial Effects of Curcumin. Full Text
Curcumin: A Potent Protectant against Esophageal and Gastric Disorders. Full Text
Effects of Prolonged Dietary Curcumin Exposure on Skeletal Muscle Biochemical and Functional Responses of Aged Male Rats. Full Text
Curcumin and its Potential for Systemic Targeting of Inflamm-Aging and Metabolic Reprogramming in Cancer. Full Text
Curcumin ameliorates chronic renal failure in 5/6 nephrectomized rats by regulation of the mTOR/HIF-1α/VEGF signaling pathway. Full Text

Fisetin – a flavonoid found in highest concentration in strawberries. Senolytic, anti-inflammatory, neuro-protective & Sirt1 activator. I take 100mg daily.

Mitigative effects of the bioactive flavonol Fisetin on high-fat/high-sucrose induced nonalcoholic fatty liver disease in rats. Full text
Fisetin ameliorates oxidative stress, inflammation and apoptosis in diabetic cardiomyopathy. Full Text

Nicotinamide MonoNucleotide (NMN) – newer NAD+ precursor. I take 250mg daily.

Nicotinamide adenine dinucleotide emerges as a therapeutic target in aging and ischemic conditions. Full Text
Drugs targeting SIRT1, a new generation of therapeutics for osteoporosis and other bone related disorders? Full Text
Role of endothelial NAD+ deficiency in age-related vascular dysfunction. Full Text
Stabilizing ends of chromosomes could treat age-related disease
Telomere Dysfunction Induces Sirtuin Repression that Drives Telomere-Dependent Disease. Full Text

Nicotinamide Riboside (NR) – NAD+ precursor.

The NAD-Booster Nicotinamide Riboside Potently Stimulates Hematopoiesis through Increased Mitochondrial Clearance. Full Text
NAD+ supplementation rejuvenates aged gut adult stem cells. Full Text
Nicotinamide riboside protects against liver fibrosis induced by CCl4 via regulating the acetylation of Smads signaling pathway. Full Text

Pterostilbene – found in blueberries. Anti-oxidant, anti-inflamatory and Sir1 activator. Similar to, but with greater bioavailability than resveratrol. Took some last year (50mg) and will order again. Works better in conjunction with NAD+ precursors.

Differential proteomic profiling identifies novel molecular targets of Pterostilbene against experimental diabetes. Full Text

Resveratrol – found in the skin of grapes. Anti-oxidant, anti-inflamatory and Sir1 activator. Took a low dose last year (50mg), will order again. Works better in conjunction with NAD+ precursors & Spermidine.

*Can Resveratrol supplement change inflammatory mediators? A systematic review and meta-analysis on randomized clinical trials. Full Text
*Resveratrol supplementation significantly influences obesity measures: a systematic review and dose-response meta-analysis of randomized controlled trials. Full Text
Resveratrol prevents the development of high blood pressure in spontaneously hypertensive rats through the inhibition of enhanced expression of Giα proteins.
Resveratrol attenuates metabolic, sperm, and testicular changes in adult Wistar rats fed a diet rich in lipids and simple carbohydrates. Full Text
Resveratrol prevents cognitive deficits by attenuating oxidative damage and inflammation in rat model of streptozotocin diabetes induced vascular dementia. Full Text
Systemic treatment with Resveratrol alleviates adjuvant arthritis-interstitial lung disease in rats via modulation of JAK/STAT/RANKL signaling pathway. Full Text

Spermidine – found in wheat germ and a potent inducer of autophagy, it works in synergy with Resveratrol. I try to eat a couple of tablespoons of wheat germ every day.

Spermidine confers liver protection by enhancing NRF2 signaling through a MAP1S-mediated non-canonical mechanism. Full Text
Spermidine and Voluntary Activity Exert Differential Effects on Sucrose- Compared with Fat-Induced Systemic Changes in Male Mice. Full Text
Dietary and Gut Microbiota Polyamines in Obesity- and Age-Related Diseases. Full Text

Prescription Supplements

Rapamycin – first drug proven to increase the health & lifespan of mice. Currently used for organ transplantation and against cancer. Have taken four doses of 2.5mg and will now move up to 3.75mg.
The first study shows how Rapamycin improves the quality of protein production in our cells. The second is an interesting hypothesis on how Rapamycin might prevent both cancer and Alzheimer’s, while the third shows that Rapamycin might work in addition to dietary restriction as oppose to just replicating its results.

Regulation of the Elongation Phase of Protein Synthesis Enhances Translation Accuracy and Modulates Lifespan. Full Text
Alzheimer's Disease and Cancer: When Two Monsters Cannot Be Together. Full Text
Is Rapamycin a Dietary Restriction Mimetic? Full Text
Rapamycin Induced Autophagy Inhibits Inflammation-Mediated Endplate Degeneration by Enhancing Nrf2/Keap1 Signalling of Cartilage Endplate Stem Cells. Full Text
Differential Effects of Rapamycin and Metformin in Combination with Rapamycin on Mechanisms of Proteostasis in Cultured Skeletal Myotubes. Full text
Caloric Restriction Mimetics against Age-Associated Disease: Targets, Mechanisms, and Therapeutic Potential. Full Text
Rapamycin induced miR 30a downregulation inhibits senescence of VSMCs by targeting Beclin1. Full Text
Activation of mTORC1/PGC1 axis promotes mitochondrial biogenesis and induces cellular senescence in the lung epithelium. Full Text
Rapamycin Inhibited Photoreceptor Necroptosis and Protected the Retina by Activation of Autophagy in Experimental Retinal Detachment. Full Text
Rapamycin Removes Damaged Mitochondria and Protects Human Trabecular Meshwork (TM-1) Cells from Chronic Oxidative Stress (Glaucoma). Full Text
Cellular senescence in progenitor cells contributes to diminished remyelination potential in progressive multiple sclerosis. Full Text
mTORC1 underlies age-related muscle fiber damage and loss by inducing oxidative stress and catabolism. Full Text
Quantitative Systems Pharmacological Analysis of Drugs of Abuse Reveals the Pleiotropy of Their Targets and the Effector Role of mTORC1. Full Text

Senolytics – not supplements or available now, but the most exciting area of anti-research at the moment. I intend to take the plunge into senolytics within the next year, before giving them to my parents:

Pharmacological clearance of senescent cells improves survival and recovery in aged mice following acute myocardial infarction. Full Text
Aged-senescent cells contribute to impaired heart regeneration. Full Text
Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Full Text
Senolytics and senostatics as adjuvant tumour therapy. Full Text
Systemic clearance of p16INK4a -positive senescent cells mitigates age-associated intervertebral disc degeneration. Full Text

A few months ago, in the comment section of a blog, somebody posted that their lab had successfully managed to rejuvenate old rats by using a fraction of young blood plasma. Young blood/plasma, along with epigenetic reprogramming, is one of the few anti-aging strategies which has the potential to be a “silver bullet” to cure ageing. The blog poster has now shared their first results with the blog in question. If the results are to be believed, and it’s a big IF as the study only involved 6 rats and has not yet been peer-reviewed, let alone replicated, then it could portend human rejuvenation being less than a decade away.
Rumors of Age Reversal: The Plasma Fraction Cure Study Results

On a personal level, in the past month I’ve gone “all in” on anti-ageing supplements with the start of me taking Rapamycin (2.5mg/weekly) & Metformin (500mg/daily). Not expecting anything myself, but I want to be confident about their safety before giving them to my parents. I bought blood pressure and blood glucose monitors to try to get some biomarkers for what it’s worth.

Below you will find February’s most interesting developments as well as a couple of really cool podcasts. Furthermore, in the supplemental attachment there are some human studies of Curcumin, Nicotinamide Riboside (NR) and Resveratrol – along with an avalanche of promising studies on Rapamycin amongst others.
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February Round-Up

Young bone marrow rejuvenates aging mouse brains - Transplanting bone marrow from young lab mice to old mice preserves memory and learning skills. This is similar to using “young blood” to treat ageing, but instead of transfusing blood, the blood producing cells have been transplanted. Full Text

CRISPR/Cas9 therapy can suppress aging, enhance health and extend life span in mice - Researchers have developed a new gene therapy to help decelerate the aging process. The findings highlight a novel CRISPR/Cas9 genome-editing therapy that can suppress the accelerated aging observed in mice with Hutchinson-Gilford progeria syndrome, a rare genetic disorder that also afflicts humans. This is the first time to my knowledge that CRISPR/Cas9 gene editing has been used in the ageing field – exciting stuff! Full text

New molecules reverse memory loss linked to depression, aging - New therapeutic molecules show promise in reversing the memory loss linked to depression and aging. These molecules not only rapidly improve symptoms, but remarkably, also appear to renew the underlying brain impairments causing memory loss in preclinical models. Full Text

Inhibition of ‘jumping genes’ promotes healthy ageing - DNA sequences called retrotransposons can copy themselves and reintegrate at new sites in the genome, causing damage. It now seems that inhibiting this process can prevent age-related health decline in mice. Full Text

Skin Repair Eliminates ‘Inflamm-Aging’ Linked to Chronic Disease In a pilot study, treatment with a full-body reparative skin cream reduced inflammatory cytokines linked to Alzheimer’s, Heart Disease and Diabetes. Time to slap on the skin cream! Full Text
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Below are two podcasts with leading anti-ageing researcher David Sinclair, who shot to fame in the mid-2000s with the red wine molecule Resveratrol, which lengthened the life of obese mice. Since then his lab has worked on the NAD+ pathway, which is vital for numerous repair processes and declines with age, and small molecules which can return NAD+ to youthful levels. He has been a big proponent of Nicotinamide Mononucleotide (NMN) to do so.

The Joe Roggan Experience – an accessible and entertaining podcast for the layman. This show caused a surge in NMN sales.

Peter Attia – a much more technical podcast getting into the nitty-gritty NAD+, NMN & ageing in general.
https://peterattiamd.com/davidsinclair/

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Research Institutes:
SENS Research Foundation (I have a recurring monthly donation)
Buck Institute
Private initiatives:
Age-Reversal Network (good information & forums for those interested in self-experimentation – this is where I found how to get non-prescription Rapamycin)
Better Humans
Lifespan.io (I have a recurring monthly donation)
Further sources of information:
Fight Aging!
Life Extension Advocacy Foundation
Longecity (good forums where the self-experimenters reside!)

======================================================================================================================

Supplemental Information

**Disclaimer – As should be self-evident to anyone receiving these emails, I am NOT a doctor or indeed a scientist. All the information pertained within is for information purposes only; use at your own risk. Please consult with a healthcare practitioner if needing medical advice.**

*Also bear in mind that most of the studies mentioned below are in rodents, not humans. Rodents, needless to say, do not always react the same way to drugs as humans do – witness the countless times cancer or another disease has been cured in rodents only to subsequently fail human trials. I have *bolded any human trials.*
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Lifestyle

Fasting – certainly the cheapest & also one of the most effective anti-ageing interventions currently available. It comes in many flavours, but I fast for at least 12 hours every day.
Autophagy and aging: Maintaining the proteome through exercise and caloric restriction. Full Text Interesting how exercising and caloric restriction work on the same pathways as the drug Rapamycin.

Non-prescription Supplements (in alphabetical order)

Astaxanthin – which is behind the pink colour of salmon & shrimp. Considered the most powerful carotinoid, it has anti-oxidative, anti-inflamatory, neuro-protective and skin-protective qualities. I take 4mg daily.

Protective effect of astaxanthin against contrast-induced acute kidney injury via SIRT1-p53 pathway in rats. Full Text
Neuroprotective role of astaxanthin in hippocampal insulin resistance induced by Aβ peptides in animal model of Alzheimer's disease. Full Text
Astaxanthin supplementation modulates cognitive function and synaptic plasticity in young and aged mice. Full Text
Astaxanthin Ameliorates Lipopolysaccharide-Induced Neuroinflammation, Oxidative Stress and Memory Dysfunction through Inactivation of the Signal Transducer and Activator of Transcription 3 Pathway. Full Text
Astaxanthin ameliorates renal interstitial fibrosis and peritubular capillary rarefaction in unilateral ureteral obstruction. Full Text
Effects of astaxanthin supplementation in healthy and obese dogs. Full Text

Curcumin – the spice which gives curries their yellow colour. Anti-inflammatory and neuroprotective. I take 1 gram a day. Needs gto be
taken with black pepper to improve bio-availability.

*The therapeutic potential of curcumin: A review of clinical trials. Full Text
*The effects of curcumin-containing supplements on biomarkers of inflammation and oxidative stress: A systematic review and meta-analysis of randomized controlled trials. Full Text
*Effects of hot water extract of Curcuma longa on human epidermal keratinocytes in vitro and skin conditions in healthy participants: A randomized, double-blind, placebo-controlled trial. Full Text
Curcumin ameliorated myocardial infarction by inhibition of cardiotoxicity - rat model. Full Text
Curcumin prevents high glucose damage in retinal pigment epithelial cells through ERK1/2-mediated activation of the Nrf2/HO-1 pathway Full Text
Curcumin improves exercise performance of mice with coronary artery ligation-induced HFrEF: Nrf2 and antioxidant mechanisms in skeletal muscle Full Text
Curcumin promotes burn wound healing in mice by upregulating caveolin-1 in epidermal stem cells Full text
Curcumin, the golden spice in treating cardiovascular diseases. Full Text
Antioxidant effects of curcumin in models of neurodegeneration, aging, oxidative and nitrosative stress: A review. Full Text
A Review of Curcumin and Its Derivatives as Anticancer Agents. Full Text

Fisetin – a flavonoid found in highest concentration in strawberries. Senolytic, anti-inflammatory, neuro-protective & Sir1 activator. I
newly take 100mg daily.

Fisetin ameliorates oxidative stress, inflammation and apoptosis in diabetic cardiomyopathy. Full Text
Fisetin rescues retinal functions by suppressing inflammatory response in a DBA/2J mouse model of glaucoma. Full Text
Activated TNF-α/RIPK3 signaling is involved in prolonged high fat diet-stimulated hepatic inflammation and lipid accumulation: inhibition by dietary fisetin intervention. Full Text
Nrf2⁻ARE Signaling Acts as Master Pathway for the Cellular Antioxidant Activity of Fisetin. Full Text
Protective effect of Fisetin on acetaminophen-induced hepatotoxicity in vitro and in vivo. Full Text
Fisetin and telmisartan each alone or in low-dose combination alleviate OVA-induced food allergy in mice. Full Text

Nicotinamide MonoNucleotide (NMN) – newer NAD+ precursor. I take 250mg daily.

Nicotinamide mononucleotide alters mitochondrial dynamics by SIRT3-dependent mechanism in male mice. Full Text
Targeting NAD+ Metabolism as Interventions for Mitochondrial Disease. Full Text
Enhanced SIRT6 activity abrogates the neurotoxic phenotype of astrocytes expressing ALS-linked mutant SOD1. Full Text
Nicotinamide adenine dinucleotide emerges as a therapeutic target in aging and ischemic conditions. Full Text

Nicotinamide Riboside (NR) – NAD+ precursor.

*Acute nicotinamide riboside supplementation improves redox homeostasis and exercise performance in old individuals: a double-blind cross-over study. Full Text

Pterostilbene – found in blueberries. Anti-oxidant, anti-inflamatory and Sir1 activator. Similar to, but with greater bioavailability than resveratrol. Took some last year (50mg) and will order again. Works better in conjunction with NAD+ precursors.

Pterostilbene Improves Cognitive Performance in Aged Rats: An in Vivo Study. Full Text

Resveratrol – found in the skin of grapes. Anti-oxidant, anti-inflamatory and Sir1 activator. Took a low dose last year (50mg), will order again. Works better in conjunction with NAD+ precursors.

*Effect of resveratrol supplementation on lipid profile in subjects with dyslipidemia: A randomized double-blind, placebo-controlled trial. Full Text
*No beneficial effects of resveratrol supplementation on atherogenic risk factors in patients with nonalcoholic fatty liver disease. Just to prove I don’t just give only positive results, in this study there were no beneficial effects.
*Health benefits of resveratrol: Evidence from clinical studies. Full Text
*The Effects of Resveratrol in Patients with Cardiovascular Disease and Heart Failure: A Narrative Review. Full Text
Health benefits of resveratrol administration. Full Text
Resveratrol as a Multifunctional Topical Hypopigmenting Agent. Full Text

Spermidine – found in wheat germ and a potent inducer of autophagy. Try to eat a couple of tablespoons of wheat germ every day.

Spermidine and Voluntary Activity Exert Differential Effects on Sucrose- Compared with Fat-Induced Systemic Changes in Male Mice. Full Text

Prescription Supplements

Rapamycin – first drug proven to increase the health & lifespan of mice. Currently used for organ transplantation and against cancer. Taken 3 doses of 2.5mg so far with nothing to report. I will increase my dose to 3.75mg after the next one.

Pharmacological inhibition of mTORC1 but not mTORC2 protects against human disc cellular apoptosis, senescence, and extracellular matrix catabolism through Akt and autophagy induction. Full Text
Next generation strategies for geroprotection via mTORC1 inhibition. Full Text
The mTORC1-autophagy pathway is a target for senescent cell elimination. Full Text In light of all the recent excitement regarding senolytic drugs, it appears that Rapamycin might also be senolytic, which would account for some of its positive effects.
mTOR inhibition by metformin impacts monosodium urate crystal-induced inflammation and cell death in gout: a prelude to a new add-on therapy? Full Text
Rapamycin attenuates articular cartilage degeneration by inhibiting β-catenin in a murine model of osteoarthritis. Full Text
Inhibition of upper small intestinal mTOR lowers plasma glucose levels by inhibiting glucose production. Full Text
Balancing mTOR Signaling and Autophagy in the Treatment of Parkinson's Disease. Full Text
Snapshot: Implications for mTOR in Aging-related Ischemia/Reperfusion Injury. Full Text
Rapamycin Confers Neuroprotection Against Aging-Induced Oxidative Stress, Mitochondrial Dysfunction, and Neurodegeneration in Old Rats Through Activation of Autophagy. Full Text
mTOR signalling: jack-of-all-trades Full Text
Measuring biological age in mice using differential mass spectrometry. Full Text This study is interesting in that giving Rapamycin to the mice reduced their biological age by 18% using their measures.
Single injection of rapamycin blocks post-food restriction hyperphagia and body-weight regain in rats. Rats didn’t regain weight after going off a diet.
Combinatorial Tissue Engineering Partially Restores Function after Spinal Cord Injury. Full Text

Senolytics – not supplements or available now, but the most exciting area of anti-research at the moment. Didn’t want to clog up the main email, so I’ve put any extra studies or news here:

Approaches towards Longevity: Reprogramming, Senolysis, and Improved Mitotic Competence as Anti-Aging Therapies. Full Text
Removing Senescent Cells Improves Heart Health

Firstly, if you haven’t backed up your hard drive recently – do it NOW! A few weeks ago I lost all my music & scientific paper downloads from the past year (fortunately I did back up all my photos/videos).
Now that you’ve backed up your hard drive…

To start with, a bit of an introduction to these monthly email updates. I have taken on-board the advice that you do not want to be wading through lengthy emails, so I have divided it into 3 parts.

The first part will be brief descriptions and internet links to a handful of longevity highlights from the past month. The second will be a link to a video or podcast, not necessarily from the past month, which will bring more in-depth insights into a facet of this field. The third part, which is attached as a Word Document, is where you need to put your waders on! Here, I will be delving into the world of supplements and drugs available to take now. This will eventually morph into a supplement guide, but for now, it mainly consists of links to last month’s research into my favourite supplements. It is lengthy however!

Please let me know what you think about this format, or if there is anything that you would like included.
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January Round-up

• The most important and exciting news of the past month was the completion of the first human senolytic’s trial. Senolytics clear out senescent or “zombie cells”, which cause dysfunction, and their clearance partially rejuvenates old tissue. This first trial was a safety study in Idiopathic Pulmonary Fibrosis (a fatal lung disease) using a combination of Dasatinib (a cancer drug) & Quercetin (a food supplement). As it only had 14 patients and was of short duration, no conclusions can be drawn; however, it was safe and some overall health markers improved. Larger follow up studies are planned. Further such studies should hopefully be released later this year, giving some indication if the amazing results in animals can be replicated in humans.

• There is a search under way to discover factors in young blood which could make you younger (see GDF11 below). The latest such factor to promote rejuvenation, especially that of the liver, was discovered last month:

• For research in ageing to speed-up, we need to be able to accurately judge biological age, otherwise any human lifespan studies would take decades. Fortunately, scientists have been working on such ageing “clocks” and the most advanced yet, which can supposedly show how much longer you have left to live, was released last month:

• One of my biggest bugbears in ageing research has been the fact that interventions are usually applied individually, whereas they need to be combined as ageing is so multifactorial. In this paper researchers have combined pairs of six plant-extracts (Black Cohosh, Valerian, Purple Passionflower, Ginkgo Biloba, Celeriac & White Willow) to see if they could synergistically extend the lifespan of yeast, which they successfully accomplished:

• The Interventions Testing Program (ITP), run by the US government, has been the gold standard in longevity interventions in mice. They were the first to show that Rapamycin lengthens rodent lives. Its latest paper, shows that Acarbose (a diabetes medication) also extends the lifespan of mice:

• While most people have heard of stem cells, most people don’t realize that their creation from adult tissue involves the cells being rejuvenated to a more youthful state. If the same could be done to whole animals instead of cells, then true rejuvenation would be at hand. The paper below is now the 3rd time this is being attempted, in this instance to speed up the healing of muscle injury in mice:

GDF11 – A young blood factor

As mentioned above, there​ is an ongoing search for factors in young blood which might be able to rejuvenate an older organism. The first such factor, GDF11, was discovered and caused much excitement back in 2014 by seeming to rejuvenate older mice. Since then there has been some controversy, with some scientists contesting the early results, but recently the science seems to be swinging back in its favour. However, before the science was in any way settled, one brave (crazy?) soul decided to experiment on himself and began injecting GDF11. After some initial issues, he reported some remarkable results and in the intervening four years has had over a hundred people join him. What makes this individual stand out from the usual motley of hucksters, is his insistence on fastidiously recording biomarkers, which he shares freely on his website. This transparency, as well as the fact that he’s not trying to sell the product, makes him and his results more believable. However, although very interesting, this research is still in its infancy and I would not suggest anyone trying out GDF11 themselves. I am keeping a close eye on it though. Check out the video presentation below:

Steve Perry’s Raadfest Presentation:

GDF11 Website, where all the biomarker data can be found: https://gdf11rejuvenation.com/

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Research Institutes:

SENS Research Foundation (I have a recurring monthly donation)
Buck Institute

Private initiatives:

Age-Reversal Network (good information & forums for those interested in self-experimentation – this is where I found how to get non-prescription Rapamycin)
Better Humans
Lifespan.io (I have a recurring monthly donation)

Further sources of information:

Fight Aging!
Life Extension Advocacy Foundation
Longecity

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Supplemental Information

Supplemental Introduction – Until recently, I had not paid too much attention to supplements, thinking them to be ineffectual, while focusing on longer term and more effective anti-ageing science/solutions. I thought that a healthy lifestyle was the best one could do presently. However, upon entering my 40s and noticing the ever increasing signs of ageing staring back at me, I have reappraised my thinking.

Now, there are countless numbers of supplements out there, most of which spout some miraculous claim or another, and I don’t have the time nor inclination to research them all. Only those which have some scientific backing, and thus have appeared in my science sites, have caught my attention. Therefore, the list below is by no means exhaustive. I’m sure that there must be some beneficial supplements which I am currently ignoring, but will pick up on once an important paper comes out – as the recent example of Fisetin for me shows.
You’ll notice that the formatting changes between the supplements, either giving the title of the scientific paper or just the disease/condition affected. Please let me know which format you prefer as well as if the information below is useful. My hunch is that it is a bit unwieldy at the moment, but I hope to improve on that with future updates.

**Disclaimer – As should be self-evident to anyone receiving these emails, I am NOT a doctor or indeed a scientist. All the information pertained within is for information purposes only; use at your own risk. Please consult with a healthcare practitioner if needing medical advice.**

*Also bear in mind that most of the studies mentioned below are in rodents, not humans. Rodents, needless to say, do not always react the same way to drugs as humans do – witness the countless times cancer or another disease has been cured in rodents only to subsequently fail human trials. I have bolded any human trials.*
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Lifestyle

Fasting – certainly the cheapest & also one of the most effective anti-ageing interventions currently available. It comes in many flavours, but I fast for at least 12 hours every day. Here is some scientific evidence of the molecular changes driving the beneficial effects:
Fasting speeds up metabolism & increases healthy metabolites Article

Non-prescription Supplements (in alphabetical order)

Astaxanthin – which is behind the pink colour of salmon & shrimp. Considered the most powerful carotinoid, it has anti-oxidative, anti-inflamatory, neuro-protective and skin-protective qualities. I take 4mg daily.
Inflammatory bowel disease PMC
Efficacy of high-affinity liposomal astaxanthin on up-regulation of age-related markers induced by oxidative stress in human corneal epithelial cells. PMC
Astaxanthin Attenuates Environmental Tobacco Smoke-Induced Cognitive Deficits: A Critical Role of p38 MAPK PMC
Astaxanthin but not quercetin preserves mitochondrial integrity and function, ameliorates oxidative stress, and reduces heat-induced skeletal muscle injury
Protective effects of astaxanthin on subarachnoid hemorrhage-induced early brain injury: Reduction of cerebral vasospasm and improvement of neuron survival and mitochondrial function
Astaxanthin mitigates subarachnoid hemorrhage injury primarily by increasing sirtuin 1 and inhibiting the Toll-like receptor 4 signaling pathway
Astaxanthin enhances the longevity of Saccharomyces cerevisiae (yeast) by decreasing oxidative stress and apoptosis.

Curcumin – the spice which gives curries their yellow colour. Anti-inflammatory and neuroprotective. I take 1 gram a day.
Effect of curcumin on memory impairment: A systematic review.
Curcumin prevents cigarette smoke extract induced cognitive impairment.
*Does turmeric/curcumin supplementation improve serum alanine aminotransferase and aspartate aminotransferase levels in patients with nonalcoholic fatty liver disease? A systematic review and meta-analysis of randomized controlled trials.
Curcumin reduces inflammation in knee osteoarthritis rats through blocking TLR4 /MyD88/NF-κB signal pathway.

Fisetin – a flavonoid found in highest concentration in strawberries. Senolytic, anti-inflammatory, neuro-protective & Sir1 activator. I newly take 100mg daily.
Fisetin, a potential caloric restriction mimetic, attenuates senescence biomarkers in rat erythrocytes

Nicotinamide MonoNucleotide (NMN) – newer NAD+ precursor. I take 250mg daily.
There was a lot of debate about whether NMN can enter cells on its own, or if it needed to be converted first to NR. That debate has been settled by the following paper:
NMN Enters Cells via Newly Discovered Pathway Full Paper
Neuroprotection
Aluminium Induced Bone Loss
Intestinal Ageing
Therapeutic Applications

Nicotinamide Riboside (NR) – NAD+ precursor.
Maternal Nicotinamide Riboside Enhances Postpartum Weight Loss, Juvenile Offspring Development, and Neurogenesis of Adult Offspring.

Pterostilbene – found in blueberries. Anti-oxidant, anti-inflamatory and Sir1 activator. Similar to, but with greater bioavailability than resveratrol. Took some last year (50mg) and will order again. Works better in conjunction with NAD+ precursors.
Fructose Induced Liver Fibrosis
Anti-depressant
Renal Fibrosis(1) (2)
Acetaminophen-induced liver injury

Resveratrol – found in the skin of grapes. Anti-oxidant, anti-inflamatory and Sir1 activator. Took a low dose last year (50mg), will order again. Works better in conjunction with NAD+ precursors.
Resveratrol: Twenty Years of Growth, Development and Controversy.
*Resveratrol reduces albuminuria in diabetic nephropathy: A randomized double-blind placebo-controlled clinical trial.
A Review of Resveratrol as a Potent Chemoprotective and Synergistic Agent in Cancer Chemotherapy. Article
The Effects of Resveratrol in the Treatment of Metabolic Syndrome. Article

Spermidine – found in wheat germ and a potent inducer of autophagy. Try to eat a couple of tablespoons of wheat germ every day.
Pairwise combinations of chemical compounds that delay yeast chronological aging through different signaling pathways display synergistic effects on the extent of aging delay PMC
Spermidine: a physiological autophagy inducer acting as an anti-aging vitamin in humans? PMC

Prescription Supplements

Rapamycin – first drug proven to increase the health & lifespan of mice. Currently used for organ transplantation and against cancer. My order has arrived, it’s sitting in the fridge and I’m going to start taking it soon.
Testicular injury
Urinary Disease
Subarachnoid Hemorrhage
Alzheimer’s Trial
Atherosclerosis
Osteoporosis

Senolytics – not supplements or available now, but the most exciting area of anti-research at the moment. Didn’t want to clog up the main email, so I’ve put any extra studies or news here:
UNITY Biotechnologies Selects a New Senolytic Candidate
The curcumin analog EF24 is a novel senolytic agent

1)Senolytics – the clearance of senescent or “zombie” cells, which could result in partial rejuvenation.

2)Rapamycin/mTOR inhibitors – the most powerful anti-ageing drug currently available (for those who know how to get hold of it… ?)

3)NAD+ precursors - novel, but available supplements which are starting to show useful anti-ageing effects.

4)Spermidine – inducer of autophagy (recycling within our cells), found in common foods and easily & cheaply obtainable.

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2018 was once again a year of incredible progress in the science of longevity. I am ever more certain that we will all be able to take advantage of this progress in our lifetimes, and if things progress at their current rate, it could be within the next decade. According to my disparate sources, some mind-blowing advances could even be revealed later this year - which might prove that true rejuvenation is within reach.

As an indication of where this field stands, I’ve included a couple of attachments. The first is a practical guide for early adopters/self-experimenters, from a longevity conference in September, whose steps I generally agree with. The second is a new paper from Nature - Cell Biology, reviewing “emerging rejuvenation strategies”, for those of you with a desire to delve into the science.

Personally, this was also a year of growth in my advocacy efforts. I presented last year’s review to my local Member of Parliament, contacted and joined various longevity organisations, visited a prominent longevity biotech, got the OK to write an article for mylocal newspaper, and more pertinently for you all: moved from theory into putting my ideas into practice as regards to longevity supplements/drugs. PS – I’ve also finally joined Twitter, so please follow me on @chrispollyanna1 for more prompt updates from this fast-moving field!
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1. Senolytics

Overview – Senescent Cells are cells which have reached the end of their lifespan and should have been cleared by the body, but instead, they hang around and release toxic substances, which cause damage to surrounding tissue. When they have been removed in animal models, there has been substantial improvement in various diseases and visible rejuvenation.

2018 - The list of conditions/diseases linked to Senescent Cells continues to grow, fromAlzheimer’s to Cardiovascular Disease via Chronic Obstructive Pulmonary Disease andRheumatoid Arthritis amongst many others.
The list of senolytic drug candidates also continues to grow with Fisetin (an available supplement derived from strawberries) and Azithromycin (a common antibiotic) leading the pack due to their availability and cheapness. If they pan out, we could be taking advantage of them within a few years…
Life and healthspan extension shown for the first time. Before, senolytics had been shown to improve average lifespan, now the combination of Dasatinib & Quercetin has been shown to increase maximum lifespan by 36%! And although it was too small a cohort to be statistically significant, all the mice on Fisetin outlived their controls.
Most excitingly, numerous human trials are underway, both from commercial companies like Unity (1), and research organisations like the Mayo Clinic (1)(2)(3), as well as private initiatives like the Age Reversal Network. The first results from some of these studies will become available in 2019 – as I said, exciting times!

2. Rapamycin / mTOR inhibitors

Overview – mTOR is one of the most important pathways in our bodies, which controls whether the body concentrates on growth or repair. When we are young, growth is obviously more important, however as we age, repair takes precedence. When mTOR gets inhibited, by Rapamycin for example, the body switches into repair mode, which in turn should increase our health and lifespan. Rapamycin was the first drug proven to extend the lifespan of a mammal.

2018 – The number of conditions to which Rapamycin can help continues to accumulate, with hearing loss, hair growth, emphysema, osteoporosis, blood brain barrier integrity(Alzheimer’s) and vertebral disc degeneration added last year.
The results of the second human trial of an mTOR inhibitor similar to Rapamycin were released (PDF), showing that treatment improved immune function and reduced respiratory tract infections among the elderly.
Previously, Rapamycin was only available through (expensive) prescription or by going through companies in India (which then still asked me for a prescription!), but in the last couple of months I have found a cheaper non-prescription source. As I have done my due diligence and am a firm believer in the science, I have placed an order, and soon my parents and I will be trying it out. Watch this space!

3. NAD+ Precursors

Overview – NAD+ is an essential molecule used in numerous processes including DNA repair. Its levels decline with age and raising them again has shown benefit in animal models. There are two commercially available precursors which appear to boost levels in humans as well – Nicotinamide Riboside (NR) & Nicotinamide MonoNucleotide (NMN).
In last year’s review I wrote about NR and had my parents start taking it, however, due to admittedly anecdotal evidence from some of the forums I frequent, I have switched my parents over to NMN and have started taking it myself. Be warned though – it’s not a cheap supplement. Also, there’s currently a scientific battle taking place as to which supplement is better, with no consensus having been reached thus far. The unpublished sources I’m following seem to be leaning towards NMN however…

2018 – One major study in mice showed an improvement in blood flow to muscles and increased exercise endurance in mice given NMN. Also, a 2017 study showed improved DNA repair in irradiated mice.
The crowdfunding campaign looking at a lifespan study of NMN in mice I mentioned in my last update was a resounding success. Not only did it smash through its initial and end goals, but it reached its stretch goal of $75,000! This means that all of the extra tests will be fully funded, and we will know in a few years if NMN also increases maximum lifespan in a mammal. A heartfelt thank you if you contributed to this noble cause. I donated $100 and have already received my free T-shirt! ?
As regards to NR, two more human studies were published looking at long term safetyand insulin sensitivity.

4. Spermidine

Overview – Spermidine is a molecule found in various foods which has been found to induce autophagy, a process by which our cells recycle damaged proteins as a source of fuel. A study showed that it increased the lifespan of mice and had various other health benefits, including cognition and cardiovascular. Moreover, it is readily available, with wheat germ having the highest concentration. In the last couple of years, I’ve added wheat germ to my diet, adding it to & sprinkling it over various dishes. It seems the cheapest and easiest life-extension hack & I consider it my secret weapon!

2018 – After numerous intriguing mouse studies, the first human studies came out last year. The first showed memory improvements in the elderly with Spermidine supplementation, while the second, an epidemiological study, showed reduced mortality in those with the highest spermidine-containing diet compared to those with the least. This was the equivalent of a five-year age difference.
If you have any questions, please don’t hesitate to get in touch. In the meantime, you can follow me on Twitter @Chrispollyanna1 and if you have any spare change, considering donating to some of the organisations below. Although this field has made amazing progress, it remains chronically underfunded and the best way to increase our chances of a long and healthy life is to give money to research.

Coming up in 2019 – Monthly updates (I promise this time!), plus a guide to the best longevity supplements, their cost and how to obtain them.
As ever, please feel free to forward this email to anyone who might be interested!

Research Institutes:

SENS Research Foundation (I have a recurring monthly donation)
Buck Institute

Private initiatives:

Age-Reversal Network (good information & forums for those interested in self-experimentation – this is where I found how to get non-prescription Rapamycin)
Better Humans
Lifespan.io (I have a recurring monthly donation)

Further sources of information:

#Fight Aging!
Life Extension Advocacy Foundation
Longecity

Over 200 years ago, Jöns Jacob Berzelius discovered the element selenium, which he named after the goddess of the moon, Selene. Aside from its industrial applications, selenium is an essential trace nutrient. A deficiency in selenium is a severe obstacle in areas of the world where the soil contains little selenium such as the case in the United Kingdom, Australia, New Zealand (source) and some areas of China (source) among others. It has been estimated that over 1 billion people have low selenium status.
Supplementing doses above the RDA (40 to 70 μg) is required to inhibit genetic damage and cancer (>100 μg). The most recent revision of the RDA for selenium is based on the estimated average requirement (EAR) required to maximise the antioxidant enzyme glutathione peroxidase (GPx) activity in plasma (source) and not necessarily for seleniums anticarcinogenic effects. Excessive doses of selenium may cause oxidative damage leading to genomic instability which raises the question, how much is enough? In this article, I try and find clarity regarding this question and bring transparency to selenium and its supplementation.
Americans have been advised that supplementation is not needed on the basis of the EAR and their serum concentrations being met according to the National Health and Nutrition Examination Survey (NHANES III) (source). However, selenium intake is on the decline in many areas of the world due to the effect of sulphur-based fertilisers on crops such as wheat (source).
Worldwide, up to one in seven people have been estimated to have low dietary selenium intake. Using moderate climate change projections, it has been predicted that future soil selenium losses from 58% (between the year 2080–2099). Predicted losses from croplands were even higher, with 66% of farmlands predicted to lose 8.7% selenium. These losses could increase the worldwide prevalence of selenium deficiency (source).
Selenium has a protective effect against some forms of cancer and may enhance male fertility, decrease cardiovascular disease mortality, and regulate inflammatory mediators in asthma (source). It has also been proposed that optimal selenium levels may potentially be useful for reducing the risk of atherosclerosis, cataracts, emphysema, inflammatory-immune disease, senile dementia, aging, and rheumatoid arthritis.
Selenium prevents cellular and subcellular lipids and fats from being peroxidised, which means it prevents body fats from going rancid (seen externally as “age spots” or “liver spots” called ceroid lipofuscin). Iron chelators such as desferrioxamine and antioxidants such as vitamin E, glutathione, and selenium may slow lipofuscin accumulation (source). An exclusive and indispensable role of selenium noted in that it is required to prevent hydroperoxide-induced ferroptosis, preventing fatal epileptic seizures and protecting the brain (source). A subclinical selenium deficiency seems to be associated with reduced immunocompetence, depression, thyroid imbalances and reproduction difficulties in both sexes. Mechanism of action:
Selenium is essential for the amino acid Selenocysteine, the 21st essential amino acid (source). Selenium exerts various biological functions which are found in at least 25 selenoproteins. Selenoproteins are involved in diverse roles such as stabilising the integrity of the sperm flagella and are essential for thyroid hormone metabolism aiding conversion of thyroxine (T4) to the active thyroid hormone, 3,3′5-triiodothyronine (T3). Selenium is a vital component of several significant metabolic pathways such as protection from neurodegeneration, maintaining lens cell viability, and reducing oxidative damage during aging. (source, source).
Selenium is a significant contribution to the anti-oxidant system. As a component of glutathione peroxidase, selenium acts as an antioxidant and has a sparing effect on vitamin E. Glutathione peroxidase blocks the generation of free radicals that destroy polyunsaturated fatty acids in cell membranes. Cellular and plasma glutathione peroxidase is the functional parameter used for the assessment of selenium status in the body, though hair and nails are also valuable and accurate. Selenium enhances the enzyme required for the detoxification of xenobiotic chemicals in the liver, glucuronyl transferase, and is involved in the regulation of prostaglandin synthesis and the degradation of intracellular peroxides.

Selenium is believed to encourage the immune system (source) and has been postulated to reduce the risk of cancer by a variety of mechanisms (source, source). Though, the potential benefits of selenium supplementation in tumour patients are undeniable (source). By enhancing the stability of the genome inhibiting carcinogen-induced covalent DNA adduct formation, selenium may also reduce the risk of cancer, retard oxidative damage to DNA, lipids, and proteins, retarding angiogenesis, and modulating cellular events critical in cell growth inhibition. Laboratory studies that have demonstrated oxidative stress induced by sodium selenite at high concentrations in both acute and chronic treatments of prostate cancer cells have proposed different mechanisms were involved (source). After acute exposure to selenite, cells presented mitochondrial injury and cell death, mainly by apoptosis while chronic exposure of selenium exerted its effects on human prostate cancer cells by altering the intracellular redox state, subsequently blocking the cell cycle.

Food sources:
The selenium content of foods is mostly dependant on soil levels. It can generally be found in brewers yeast, whole grains, meat, kelp, seaweed, fish and other seafood (e.g. tuna, oysters, herring), brazil nuts, garlic, milk, eggs, and kidneys that are grown or raised on selenium-rich soil.

Dose:
The RDA for selenium is 55 μg for healthy adult males and 55 to 75 μg for healthy females. The RDA for children starts at 15 μg and increases to 40 μg by the age of 9 years. The therapeutic dose range is 200 to 800 μg/day and does not lead to toxicity (source). Selenium has a narrow safety margin, with clinical toxicity reported on daily doses of 1000 to 2000 μg over a month. The dose for long-term use is believed to range between 100 to 400 μg. Extrapolation from animal experiments suggests that 400 to 700 μg/day may be needed for cancer protection. Since 400 μg daily is probably the upper limit of safety, daily doses of 100 to 200 μg may be more realistic and safe objectives for inhibiting genetic damage and carcinogenesis in humans(source, source). Such recommendations are contrary to the traditional nutritional essentiality paradigm; however, as such advice is consistent with a better health outcome, perhaps it is time that the paradigm is reviewed (source, source).
One of the safest selenium supplements is selenium organically bound to yeast. Yeast-based selenium is approximately 40% selenomethionine, 20% other amino acid conjugates (e.g., selenocysteine, methylselenocysteine), and 40% unidentified selenopeptides (source). Doses of 500 to 1000 μg have been observed to be well tolerated. Another safe form of organic selenium is selenomethionine at doses of 200mcg (source). Selenomethionine appears more effective at increasing selenium status; while selenite and selenate are more bioavailable than selenomethionine. In one animal study, co-administration of vitamin C suppressed the chemopreventive effect of inorganic selenium (selenite), but not those of selenomethionine.
Animal studies have established that the dose and form of selenium compounds are critical factors regarding circumscribing cellular responses, inorganic selenium at doses up to 10 μmol, and organic selenium compounds at doses equal to or greater than 10 μmol achieve distinctly different cellular responses (source). Animal studies using multiple different tumorigenesis models have mainly found that selenium has notable chemopreventive activity.

Clinical Uses:
Biochemical changes produced by selenium deficiency predisposes people who experience additional stresses to develop certain illnesses (source). Insufficient selenium intake has been estimated to affect up to 1 billion people worldwide (source). Selenium has cancer-protective effects (source, source, source, source). In a placebo-controlled human trial, supplementation of 200 μg selenium from 0.5 g brewer’s yeast has been determined to decrease the incidence of several types of cancers (source). This prospective study found that a daily supplement of 200 μg selenium over an average of 4.5 years revealed no protective effects against the primary endpoint of squamous and basal cell carcinomas of the skin. However, the selenium-treated group did have substantial reductions in the incidence of prostate cancer and total cancer incidence and mortality(source). This dose is three or four times the RDA.
Nevertheless, such findings are supported by epidemiologic studies, which have shown that low selenium status is associated with an increased total cancer incidence, particularly of gastrointestinal, prostate, and lung cancers (source). Surely, epidemiologic, laboratory and serendipitous results of two randomised clinical trials suggest that men with high selenium and vitamin E intake have a lower risk of prostate cancer (source). Also, a case-control study has also found that low plasma selenium is associated with a four-to-five-fold increased risk of prostate cancer (source).
It should be noted that the reduced levels of prostate-specific antigen (PSA), a commonly used marker for prostate cancer, observed with selenium supplementation are expected due to the effect of selenium on cancer cells and not because of selenium interfering with the production of PSA for any reason other than a decrease in cancer cells. A useful indicator in the disease progression in individuals is the change in serum PSA levels during selenium supplementation (source).
Since plasma selenium decreases with age, supplementation may be beneficial to older men. It appears that low selenium serum levels correlate with cancer of the head, neck (source) and lung (source). Low selenium serum levels have also been associated with increased risk of thyroid cancer and may play a role in carcinogenesis (source). Moreover, serum concentrations of selenium are significantly decreased in patients with malignant tumours (source).
While the protective effect of selenium against cancer and the low serum level of selenium is reasonably well documented, there is less clinical evidence to support the anti-inflammatory effect of selenium in arthritis. A clinical trial failed to demonstrate that selenium treatment (200 μg/day) produced any clinical benefit in the case of rheumatoid arthritis. However, when examining the quality of life, there was a significant improvement in arm movements and health feeling in selenium-treated patients (source).
The Human Immunosuppression Virus (HIV) depletes the body stores of selenium, which, in turn, cause the immune system failures manifested as Acquired Immunodeficiency Disease Syndrome (AIDS). Selenium supplementation has been shown to forestall the progression of HIV infection to developing AIDS, to reduce the symptoms of AIDS and to improve the lifespan of AIDS patients. (source, source, source)
Selenium can up-regulate genes related to phase II detoxification enzymes, certain selenium-binding proteins and select apoptotic genes, while down-regulating those related to phase I activating enzymes and cell proliferation. Independent of tissue type, selenium arrests cells in G1 phase of cell cycle, inhibits CYCLIN A, CYCLIN D1, CDC25A, CDK4, PCNA and E2F gene expressions while influencing the expressions of P19, P21, P53, GST, SOD, NQO1, GADD153 and certain CASPASES. In addition to those described above, genes such as OPN (involved in metastasis) has been reported to be down-regulated by selenium (source)
Animal studies suggest other areas for investigation. It is possible that selenium deficiency and vitamin E deficiency can activate latent viruses such as herpes (source). Animal studies have also shown that mice on either selenium or vitamin E deficient diets developed myocarditis when exposed to coxsackievirus infection; those with adequate selenium or vitamin E status did not (source). Viral-induced neuropathy was found to abate once selenium, vitamin E, carotenoid, and riboflavin blood levels were increased. It appears that a normally avirulent viral genome may become pathogenic in a nutritionally deprived host. An experimental animal study has also found that growth retardation induced by selenium deficiency is associated with impaired bone metabolism and a reduction in bone mineral density (source).
It appears that selenium is critical for healthy sperm and may improve fertility and the chance of a successful conception for both men and women. Supplementation in the case of selenium deficiencies in the procreation period of both women and men is of utmost significance to prevent gestational complications, miscarriages and the damaging of the nervous and immune systems of the fetus as well as to promote fertility (source). 56% of subfertile men with low selenium status showed a positive response to selenium supplementation, improving sperm motility and the chance of successful conception. This study highlights the inadequate provision of this essential element in the Scottish diet (source).

Hair Test Notes:
There are moderate correlations between selenium levels in whole blood, serum, toenails and hair and correlate with dietary intake assessed through nutritional records and food frequency questionnaires (source, source, source, source). Thus hair mineral analysis (HMA) may be a useful tool in monitoring selenium treatment (source) or occupational exposure (source). There is a good correlation between hair and plasma selenium levels in healthy children (source)
Selenium can protect and antagonise arsenic and has the potential to mitigate arsenic toxicity (source). As well as a mutual antagonism between mercury (source), cadmium (source), silver (source), and thallium (source, source). Excess storage of iron can be produced by deficiencies of selenium, copper, zinc, and is wrongly blamed for liver cirrhosis, fibrosis of the pancreas, hypertrophic cardiomyopathy and diabetes. These diseases are not the direct result of iron excess, but rather a deficit or biounavailability of the elements listed above.

HIGH HAIR SELENIUM
High hair selenium can be due to the use of shampoos containing selenium may indicate a loss of selenium through the hair.
LOW HAIR SELENIUM
Low hair selenium may be due to dietary deficiency, which is relatively common, especially among those who eat refined foods.

Toxicity or Drug interactions:
Selenium toxicity is increased in animals with low or depleted stores of vitamin E. Chronic ingestion of more than 0.6 mg/day can cause toxicity.

POSSIBLE SYMPTOMS OF SELENIUM TOXICITY

• Garlic breath
• Paresthesia
• Rough Hair
• Hair loss
• Nausea
• Gastric disturbances
• Brittle fingernails
• Dermatitis
• Hepatorenal damage
• A metallic taste
• Nervous irritability
• Depression
• Unusual fatigue
• Vomiting
• Lameness
• Pain
• Sloughing of skin
• Erosion of joints
• Liver cirrhosis
• Cardiac Atrophy
• Lowered conception rates
• Anemia
• Congenital disabilities
• Muscle spasms

• Less than 11mcg selenium daily is considered to unquestionably put people at risk of selenium deficiency and genetic damage (source). An increased risk of cancer is suspected of being associated with selenium deficiency. Clinically, conclusions consistent with selenium deficiency include fingernail and skin changes, cardiomyopathy (source), and skeletal muscle fatigue, tenderness, and weakness.
• Patients on monoamine inhibitors should avoid yeast-containing selenium products.
• Although an adequate vitamin C status is necessary for normal selenium metabolism, megadoses of vitamin C may decrease absorption of selenium taken as sodium selenite (source).
• Selenium deficiency could exacerbate iodine deficiency (source).
• Smoking tends to lower selenium biomarker concentrations, even though smoking is a source of selenium exposure - a phenomenon that might be related to increased excretion of the metalloid due to interaction with cadmium or other heavy metals (source, source)

• HIV (AIDS) Anemia (RBC fragility)
• Age Spots & Liver Spots–ceroid lipofuscin
• Fatigue Muscular weakness
• Myalgia (Fibromyalgia, muscle pain and soreness)
• Rhabdomyolysis (breakdown of skeletal muscle cell walls following exercise)
• Scoliosis
• Muscular Dystrophy (MD, White Muscle Disease, Stiff Lamb Disease)
• Cystic Fibrosis Cardiomyopathy (Keshan Disease, “Mulberry heart” disease)
• Multiple sclerosis (MS) Blindness – cataracts, macular degeneration Heart palpitations Irregular heart beat
• Liver cirrhosis
• Pancreatitis
• Pancreatic atrophy
• Lou Gehrig’s disease (ALS)
• Parkinson’s Disease
• Alzheimer’s Disease
• Adrenoleukodystrophy (ALD – “Lorenzo’s Oil” Syndrome)
• Infertility
• Low birth weight
• High infant mortality
• Miscarriages
• Sudden Infant Death Syndrome (SIDS)
• Cancer
• Clinical AIDS (HIV infection)
• Pathogenic viruses
• Sickle-cell anemia; thalassemia
• Wilson’s Syndrome (hypothyroidism)
• Hyperthyroidism

• Animal studies have shown selenium causes congenital disabilities when given in large doses.
• Close monitoring of patients on selenium supplementation is necessary.
• Vitamin E 500 IU enhances the efficacy of selenium.
• Selenium and vitamin E have closely related mechanisms of action, and deficiency in one often overlaps with a deficiency in the other.
• Muscular pain associated with selenium deficiency may be corrected with 200 μg daily.
• Selenium modulates T lymphocyte-mediated immune responses and stimulates peripheral lymphocytes to respond to antigens.Selenium 200 μg daily combined with beta-carotene 15 mg and vitamin E 500 IU may reduce the risk of cancer.
• Selenium does not protect against skin cancer, whether it be basal or squamous cell cancer.

• Those with low levels of selenium before selenium supplementation had a significantly lower incidence of lung cancer due to selenium supplementation (source, source)