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November 2019 Longevity Review

Posted by Chris Pollyanna , 20 December 2019 · 1,085 views

review supplements gene therapy rapamycin berberine nmn nad+ j147

November 2019 Longevity Review

 

Hello and welcome once again to this month’s longevity review. There was an important gene therapy study out this month which feeds into one of the themes of the year, whereby instead of trying a single agent against ageing, multiple ones are used. I’ve been banging on about this all year that, as ageing is a multifactorial process, we are going to need more than one intervention to make much progress. In the study below, three different gene therapies were used simultaneously in mice.

 

On a personal note, I took a day trip to the USA to pick up a prescription for legitimate Rapamycin, after the issues I had regarding strength with my previous source. Rather annoyingly however, due to a quirk in the pharmacy’s dispensing practices, I could only get enough for a seven week supply at 5mg/week. Hopefully seven weeks will be long enough for my mother to notice some beneficial effects. Although I talked above about the need for multiple therapies, Rapamycin appears to be a drug which affects multiple aspects of ageing, though it is not a cure by any means (& yes there’s more Rapamycin research news below). In addition, due to a special promotion, I’m finally getting my whole genome sequenced from Dante Labs for only $199USD. I’ve been waiting for the chance to do this since the 1990s, so I’m quite excited, even though I have no idea what I’ll do with the info!

 

A final note – I promised most of you that you would only receive a maximum of one email per month. Well, promises are meant to be broken, aren’t they? Over the coming month you’ll be receiving two additional emails. One will be a review of the year, culled from my monthly emails, with perhaps a bit of perspective, while the other will be a once in a decade review of the 2010s with a look forward to the 2020s. Hopefully with that last email, you will appreciate the amazing strides that have taken place in the longevity field as well as the tantalizing prospect of what might be in store in the next ten years.

 

Follow me on Twitter @ChrisPollyanna1 for the latest updates!

 

Or you can join my longevity Facebook group.

 

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 still have 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.

 

November Round-Up:

  • The biggest advance this month was this study in mice of using combination gene therapy to try to treat multiple different diseases. It was conducted by George Church, a titan in bio-medicine. Three different gene therapies were used in combination to try to treat type-2 diabetes, heart and kidney failure. They found that a combination of two of the gene therapies successfully treated those three conditions. This was very much an early proof of principle study. In the past, Church has talked about using 60 therapies simultaneously. They’ve now also started a trial in dogs and it could be available for humans in ten years or so according to the 60 Minute interview below.
A single combination gene therapy treats multiple age-related diseases. Full Text LEAF Review
LEAF Video Review (Journal Club)
  • Berberine, a natural product which some people use in place of Metformin, was shown in the following study to extend mouse lifespan, reduce the effect of senescent cells and improve the density and glossiness of the animals fur (quite noticeable when looking at the photos in the Full Text).
Berberine ameliorates cellular senescence and extends the lifespan of mice via regulating p16 and cyclin protein expression. Full Text
  • Here is a new study on two compounds which I’ve been tracking the last few years. I had the chance to speak to the lead author of this study at the EARD 2019 conference in July, and she told me one of them, J147, had just entered phase I human trials. In this new study, as well as preventing mitochondrial dysfunction, the two compounds significantly prevented changes in gene expression associated with aging in age accelerated mice, and as a result their cognitive function was superior to that of untreated animals.
Alzheimer's drug candidates reverse broader aging, study shows Full Text
  • And in what appears to be a monthly occurrence, a couple of more studies with Rapamycin, this time in humans. The first study tested Rapamycin topically in volunteers over 40 and resulted in among other things in a “relative improvement in clinical appearance of the skin”. The second study, in Rheumatoid Arthritis, showed some clinical improvement as well as a reduction in the need for other immunosuppressant drugs. However, just to show that I’m not glossing over bad news, there was also a disappointing result in a phase III clinical trial of a drug targeting the same pathway as Rapamycin (mTOR). I had high hopes for that trial, so it just goes to show that nothing can truly be counted on when it comes to biology.
*Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial. Full Text LEAF Review

 

*Low-Dose Sirolimus Immunoregulation Therapy in Patients with Active Rheumatoid Arthritis: A 24-Week Follow-Up of the Randomized, Open-Label, Parallel-Controlled Trial. Full Text

 

*Disappointing Results for ResTORbio Human Trial Restorbio Conference Call
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Video to watch:
Following on from this month’s top story, here is a CBS 60 Minutes interview with George Church:
https://www.cbsnews....tes-2019-12-08/

 

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November 2019 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.
Protein Quantity and Source, Fasting-Mimicking Diets, and Longevity Full Text
*Intermittent fasting increases longevity in cardiac catheterization patients
Calorie restriction slows age-related microbiota changes in an Alzheimer's disease model in female mice. Full Text
Dietary restriction improves fitness of ageing parents but reduces fitness of their offspring in nematodes. Full Text

 

Diet – let food be thy medicine…
Extra virgin olive oil improves synaptic activity, short-term plasticity, memory, and neuropathology in a tauopathy model. Full Text
*Habitual Nut Exposure, Assessed by Dietary and Multiple Urinary Metabolomic Markers, and Cognitive Decline in Older Adults: The InCHIANTI Study.
The effects of blueberry and strawberry serum metabolites on age-related oxidative and inflammatory signaling in vitro
*Effect of Protein Supplementation on Physical Performance in Older People With Sarcopenia-A Randomized Controlled Trial.
Walnut-Associated Fatty Acids Inhibit LPS-Induced Activation of BV-2 Microglia.
Ketogenic diet activates protective γδ T cell responses against influenza virus infection. Full Text
Plant-Based Dietary Patterns, Plant Foods, and Age-Related Cognitive Decline Full Text
Dietary Fat and Cardiovascular Disease: Ebb and Flow Over the Last Half Century. Full Text

 

Exercise – if you could bottle the benefits of exercise, it would be the biggest blockbuster drug of all time.
*Temporal changes in cardiorespiratory fitness and risk of dementia incidence and mortality: a population-based prospective cohort study Full Text LEAF Review
*Pilates versus resistance training on trunk strength and balance adaptations in older women: a randomized controlled trial. Full Text
*Any amount of running linked to significantly lower risk of early death
*Effects of Aging and Lifelong Aerobic Exercise on Basal and Exercise-Induced Inflammation

 

Non-prescription Supplements (in alphabetical order)
*Due to concerns about engendering homeostasis, I’ve begun varying my intake of supplements so that I’m not taking all of them every day. Haven’t worked out a rota so far.

 

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 4 or 8 mg intermittently.
Effects of Astaxanthin from Shrimp Shell on Oxidative Stress and Behavior in Animal Model of Alzheimer's Disease. Full Text
Astaxanthin protects against osteoarthritis via Nrf2: a guardian of cartilage homeostasis. Full Text
The Effects of Postoperative Astaxanthin Administration on Nasal Mucosa Wound Healing. Full Text
Maintenance of mitochondrial function by astaxanthin protects against bisphenol A-induced kidney toxicity in rats. Full Text

 

Curcumin – the spice which gives curries their yellow colour. Anti-inflammatory and neuroprotective. I take 1 gram intermittently. Needs to be taken with black pepper (piperine) to improve bio-availability.
*Effects of curcumin on cardiovascular risk factors in obese and overweight adolescent girls: a randomized clinical trial. Full Text
Combination of curcumin and luteolin synergistically inhibits TNF-α-induced vascular inflammation in human vascular cells and mice.
Curcumin Ameliorates Benzo[a]pyrene-Induced DNA Damages in Stomach Tissues of Sprague-Dawley Rats. Full Text
Curcumin Ameliorates Nonalcoholic Fatty Liver Disease through Inhibition of O-GlcNAcylation. Full Text
Chronic treatment of curcumin improves hepatic lipid metabolism and alleviates the renal damage in adenine-induced chronic kidney disease in Sprague-Dawley rats. Full Text
Curcumin inhibits cigarette smoke-induced inflammation via modulating the PPARγ-NF-κB signaling pathway.

 

Nicotinamide MonoNucleotide (NMN) – newer NAD+ precursor. I take 250 – 500mg on days I exercise.
*Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men Full Text LEAF Review
NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome. Full Text
Pharmacological restoration of autophagy reduces hypertension-related stroke occurrence. NMN not mentioned in abstract, but was used in study.
Nicotinamide mononucleotide does not protect the ovarian reserve from cancer treatments.

 

Nicotinamide Riboside (NR) – NAD+ precursor.
*Effects of Nicotinamide Riboside on Endocrine Pancreatic Function and Incretin Hormones in Nondiabetic Men With Obesity.
*Nicotinamide riboside does not alter mitochondrial respiration, content or morphology in skeletal muscle from obese and insulin resistant men.

 

Pterostilbene – found in blueberries. Anti-oxidant, anti-inflamatory and Sir1 activator. Similar to, but with greater bioavailability than resveratrol. Taking 50mg intermittently in the same pill as resveratrol. Works better in conjunction with NAD+ precursors.
PGC1α activation by pterostilbene ameliorates acute doxorubicin cardiotoxicity by reducing oxidative stress via enhancing AMPK and SIRT1 cascades. Full Text
Pterostilbene Attenuates Experimental Atherosclerosis through Restoring Catalase-Mediated Redox Balance in Vascular Smooth Muscle Cells.

 

Resveratrol – found in the skin of grapes. Anti-oxidant, anti-inflamatory and Sir1 activator. Taking 250mg intermittently in the same pill as pterstilbene. Works better in conjunction with NAD+ precursors & Spermidine.
Resveratrol Supplementation Protects Against Nicotine-Induced Kidney Injury. Full Text
Combinatorial therapeutic effect of resveratrol and piperine on murine model of systemic lupus erythematosus
The Fluid Aspect of the Mediterranean Diet in the Prevention and Management of Cardiovascular Disease and Diabetes: The Role of Polyphenol Content in Moderate Consumption of Wine and Olive Oil. Full Text
Resveratrol delay the cataract formation against naphthalene-induced experimental cataract in the albino rats.
The synergy of resveratrol and alcohol against Helicobacter pylori and underlying anti-Helicobacter pylori mechanism of resveratrol
*The Effects of Resveratrol on Oxidative Stress Markers: A Systematic Review and Meta-Analysis on Randomized Clinical Trials.

 

Spermidine found in wheat germ and a potent inducer of autophagy, it works in synergy with Resveratrol. I try to eat a few of teaspoons of wheat germ every day in my berry & nut breakfast.
Longevity in response to lowered insulin signaling requires glycine N-methyltransferase-dependent spermidine production. Full Text
Polyamines reverse immune senescence via the translational control of autophagy.

 

Other available supplements
Quercetin, caffeic acid and resveratrol regulate circadian clock genes and aging-related genes in young and old human lung fibroblast cells.
Melatonin modulates IL-1β-induced extracellular matrix remodeling in human nucleus pulposus cells and attenuates rat intervertebral disc degeneration and inflammation. Full Text
Melatonin: A review of its potential functions and effects on neurological diseases.
Dietary alpha-ketoglutarate promotes beige adipogenesis and prevents obesity in middle-aged mice. Full Text
Protective Effects of Silymarin Against Age-Related Hearing Loss in an Aging Rat Model.

 

Prescription Supplements

 

MetforminAnti-diabetic medication, maintained by many scientists to be a safe longevity enhancing medication. I’m still on the fence about this (see September’s newsletter).
*Metformin increases fasting glucose clearance and endogenous glucose production in non-diabetic individuals Full Text
Metformin decreases LPS-induced inflammatory response in rabbit annulus fibrosus stem/progenitor cells by blocking HMGB1 release. Full Text

 

Rapamycin (sirolimus) – first drug proven to increase the health & lifespan of mice. Currently used for organ transplantation and against cancer. Was taking 5mg (or only 3.23mg?) once a week before my source’s legitimacy was questioned, stopped & have yet to resume.
mTOR drives cerebrovascular, synaptic, and cognitive dysfunction in normative aging. Full Text
Stimulation of autophagy improves vascular function in the mesenteric arteries of type 2 diabetic mice Full Text
Rapamycin regulates the balance between cardiomyocyte apoptosis and autophagy in chronic heart failure by inhibiting mTOR signaling. Full Text
Antileishmanial effect of rapamycin as an alternative approach to control Leishmania tropica infection
Randomized Multicenter Trial of Sirolimus vs. Prednisone as Initial Therapy for Standard Risk Acute GVHD: BMT CTN 1501
STAT3-miR-17/20 Signaling Axis Plays a Critical Role in Attenuating Myocardial Infarction following Rapamycin Treatment in Diabetic mice.
mTOR signaling in Brown and Beige adipocytes: implications for thermogenesis and obesity. Full Text
mTORC1 signalling is not essential for the maintenance of muscle mass and function in adult sedentary mice. Full Text
Autophagy inhibits the mesenchymal stem cell aging induced by D-galactose through ROS/JNK/p38 signaling.
Rapamycin could increase the effects of melatonin against age-dependent bone loss.

 

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:
Targeting senescent cells in translational medicine Full Text
Long-Term Clearance of Senescent Cells Prevents the Hematopoietic Stem Cell Aging in Naturally Aged Mice
Senescent synovial fibroblasts accumulate prematurely in rheumatoid arthritis tissues and display an enhanced inflammatory phenotype. Full Text
Targeting senescent cells: approaches, opportunities, challenges Full Text

 

Epigenetic Cellular Reprogramming/Aging Clocks – 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:
DNA methylation aging clocks: challenges and recommendations. Full Text
Deep biomarkers of aging and longevity: from research to applications. Full Text
A meta-analysis of genome-wide association studies of epigenetic age acceleration. Full Text

 

Telomeres the protective caps on the end of our chromosomes. Their shortening over time has been seen by some as either an ageing “clock”, or indeed as a driver of ageing itself. I’m very much on the fence about this. There were however a large number of studies this month, so I decided to group them together.
*Correlation between Telomere Attrition of Zona Fasciculata and Adrenal Weight Reduction in Older Men
*Marital status, telomere length and cardiovascular disease risk in a Swedish prospective cohort.
*Plant-Rich Dietary Patterns, Plant Foods and Nutrients, and Telomere Length Full Text
*Independent and Combined Effects of Telomere Shortening and mtDNA4977 Deletion on Long-term Outcomes of Patients with Coronary Artery Disease Full Text

 

Odds & Sods
Slower rates of accumulation of DNA damage in leukocytes correlate with longer lifespans across several species of birds and mammals. Full Text
Functional microbiome deficits associated with ageing: Chronological age threshold. Full Text LEAF Review
Neurogenesis and prolongevity signaling in young germ-free mice transplanted with the gut microbiota of old mice LEAF Review
Could cytotoxic T-cells be a key to longevity?
Rotating magnetic field delays human umbilical vein endothelial cell aging and prolongs the lifespan of Caenorhabditis elegans. Full Text
Advancements to the Axolotl Model for Regeneration and Aging Full Text
Childhood intelligence attenuates the association between biological ageing and health outcomes in later life. Full Text
Playing analog games is associated with reduced declines in cognitive function: a 68 year longitudinal cohort study. Full Text
Agephagy - Adapting Autophagy for Health During Aging. Full Text







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