Articles - Articles

Aging Theories: is an 'aging program' a...

Wed, 18 Apr 2018 18:00:26 +0000

The big and continuing mystery about aging has been as described by Vit Zemanek in his recent Longecity article [1]
“When Darwin’s theory of evolution by natural selection was established, biologists were puzzled by the existence of senescence and aging among all organisms.
Why did the evolutionary pressure not produce immortal species?”

A further question might be: why does aging ‘look’ so much like other evolved traits? Why is it that aging (and internally determined lifespan) varies between individual members of a species and varies to a much greater extent between different species?
Unfortunately Zemanek’s account ends prior to the development of modern programmed aging theories, which are emerging as a major force in developing anti-aging medicine.
Programmed aging theories contend that organisms have developed biological mechanisms (“programs”) that purposely limit individual lifespans in order to obtain an evolutionary benefit for a population of individuals that possess the program. Organisms -including humans- possess what amounts to a biological ‘suicide mechanism’. The drastic increase with age seen in highly age-related diseases and conditions is the result of this ‘aging program’.

Some theorists have supported the idea that a trait (like programmed aging) can evolve to benefit a population even at the expense of individual members [6]. “Benefit” in this case means increasing the probability that the population will expand, escape extinction, and produce descendant species.
But does the evolution process operate to benefit a population, or individual members of a population? Many proponents of non-programmed theories such as Tom Kirkwood, (author of the disposable soma theory [4]), dismissed programmed aging theories and other theories based on population benefit because of the conflict with Darwin’s evolutionary mechanics. Some analyses in the 1960’s [10] were also cited as definitively defeating population benefit concepts such as group selection (first proposed in 1962), kin selection, and small-group selection. August Weismann originally considered programmed aging in 1882 [5] but eventually changed his position. A series of aging theories are based on population-oriented evolutionary mechanics concepts originated by Peter Medawar in 1952 [2]. He proposed that the lifespan needed by an organism is highly dependent on species and population-specific circumstances such as age at reproductive maturity and extent of predation. Other authors of the early population benefit theories (e.g. [11) were mainly trying to explain other observed discrepancies with Darwinian mechanics such as animal altruism and were therefore relatively unconcerned with theoretical gerontology.
However today there are multiple aging theories based on population benefit [6,7,8,9]). Some [6] specifically propose solutions for the evolutionary mechanics issues based on modern genetics discoveries that support population benefit and thereby programmed aging.
One can compare published efforts (e.g. [12] and [13]) to contradict the new programmed theories as well as counter arguments (e.g. [15,16,17,18]). Note that many modern non-programmed aging theories also require population-oriented modifications to Darwin’s mechanics.

Empirical observations that may favour programmed theories include:
• Explicit suicide mechanisms have been found in some organisms such as octopus [21] and roundworm [22].
• Human genetic diseases Hutchinson-Guilford progeria and Werner’s syndrome simultaneously accelerate many or most symptoms of aging including age-related diseases [23] suggesting a defect in a common mechanism that controls the diverse symptoms.
• Genetic engineering has produced roundworms that live 10 times as long as wild worms [24] suggesting existence of a program.
• Some species (e.g. Pacific rockfish) have been identified that apparently do not age [25]. This is a problem for non-programmed aging theories that have difficulties explaining why an apparently internally immortal species would exist. Programmed theories suggest these species could be the result of a fault (e.g. mutation) that disabled their program and therefore increased the probability that the population would become extinct [19].

Why is this theoretical question of such crucial relevance?
The programmed vs. non-programmed issue is critically important to medical efforts toward dealing with aging and age-related diseases precisely because of the “unifying factor” question.
As described by antagonistic pleiotropy theory author George Williams in 1957 [3], nonprogrammed theories strongly suggest that there is no treatable common cause of the many different age-related diseases and conditions and thus no unifying factor. Western medicine is largely based on the idea that each individual age-related disease or condition has different causes that need different treatments. Non-programmed theories strongly support this view. Programmed theories strongly suggest that there are common factors (elements of the program mechanism) behind the different age-related diseases and conditions.
I argue that the emergence of modern programmed aging theories provides a sound theoretical basis for new approaches in developing medical treatments for highly age-related diseases and conditions as well as a basis for the idea that human lifespan can be generally increased.

References:

1 Zemanek V. Aging theories: Is there a unifying factor in aging? Longecity
2 Medawar, P.B, An Unsolved Problem of Biology., 1952. H.K. Lewis & Co., London.
3 Williams, G Pleiotropy, natural selection and the evolution of senescence,. 1957. Evolution 11, 398-411
4 Kirkwood T.B.L. & F.R.S. Holliday, The evolution of ageing and longevity, 1979. Proceedings of the Royal Society of London B 205: 531-546
5 Weismann A. Uber die Dauer des Lebens. 1882 Fischer, Jena
6 Goldsmith T. (2017) Evolvability, Population Benefit, and the Evolution of Programmed Aging in Mammals. Biochemistry (Moscow), 2017,Vol. 82, No. 12, pp. 14231429 DOI:10.1134/S0006297917120021
7 Skulachev V. Aging is a Specific Biological Function Rather than the Result of a Disorder in Complex Living Systems: Biochemical Evidence in Support of Weismann's Hypothesis. Biochemistry (Mosc). 1997 Nov;62(11):1191-5. PMID: 9467841
8 Libertini G (1988) An adaptive theory of increasing mortality with increasing chronological age in populations in the wild. J. Theor. Biol. 132. 145-162.
9 Mittledorf J. Chaotic Population Dynamics and the Evolution of Ageing. Evolutionary Ecology Research 2006, 8: 561-574
10 Williams G. Adaptation and Natural Selection: A Critique of Some Current Evolutionary Thought, Princeton UP. ISBN 0-691-02357-3 1966
11 Wynne-Edwards V. Animal Dispersion in Relation to Social Behaviour, Edinburgh: Oliver & Boyd, 1962
12 Kowald A, Kirkwood T. Can aging be programmed? A critical literature review Aging Cell 2016 doi: 10.1111/acel.12510
13 Kirkwood T, Melov S. On the programmed/non-programmed nature of ageing within the life history. Curr Biol. 2011 Sep 27;21(18):R701-7. doi: 10.1016/j.cub.2011.07.020
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15 Goldsmith T. On the programmed/ non-programmed aging controversy Biochemistry (Moscow) 2012 Vol 77 Nr 7 729-7322012 doi: 10.1134/S00629791207005X PMID: 22817536
16 Goldsmith T Aging is programmed! (A response to Kowald-Kirkwood “Can aging be programmed? A critical literature review”) DOI: 10.13140/RG.2.2.36205.38883
17 Skulachev V. Aging as a particular case of phenoptosis, the programmed death of an organism (a response to Kirkwood and Melov "On the programmed/non-programmed nature of ageing within the life history"). Aging (Albany NY). 2011 Nov;3(11):1120-3
18 Goldsmith T. Arguments against non-programmed aging theories Biochemistry (Moscow) Phenoptosis 78:9 971-978 2013
19 Goldsmith T. The Evolution of Aging – 3 rd ed. 2014 Azinet Press Annapolis ISBN 9780978870959
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21 Wodinsky J. 1977. Hormonal inhibition of feeding and death in octopus: control by optic
gland secretion. Science, 198: 948–951.
22 Apfeld J, Kenyon C. Regulation of lifespan by sensory perception in Caenorhabditis elegans. Nature 1999.
23 Gray, Md; Shen, Jc; Kamath-Loeb, As; Blank, A; Sopher, Bl; Martin, Gm; Oshima, J; Loeb, La (Sep 1997). The Werner syndrome protein is a DNA helicase. Nature genetics 17 (1): 100–3.
doi:10.1038/ng0997-100. PMID 9288107
24 Kenyon, C. Regulation of Life-Span by Germ-Line Stem Cells in Caenorhabditis elegans, , Science (Vol. 295, 18 January 2002)
25 Bennett, J.T. et al. Confirmation on longevity in Sebastes diploproa (Pisces: Scorpaenidae) from 210Pb/226Ra measurements in otoliths. 1982. Maritime Biology. 71, 209-215.

further material at http://aging-theories.org

Antioxidants- relevant for life extension?

Sun, 18 Feb 2018 23:36:23 +0000

Harman published his free radical theory of aging in 1956 and in the following decades it slowly became probably the most popular explanation of the mechanism of aging (Ashok & Ali, 1999). Because the theory claims that reactive oxygen species damage macromolecules (more details in my previous article “Aging theories: Is there a unifying factor in aging?”), the effects of substances known as nutritional antioxidants have received a lot of attention. The underlying theory that has been long accepted says that antioxidants may improve health (and eventually prolong lifespan) by lowering the level of oxidative stress present in the organism because they eliminate free radicals, usually by 'donating' a free electron.
However, there is a controversy about validity of this theory because some researchers reached the opposite conclusion. They view reactive oxygen species as signal molecules important for mitochondrial processes and cellular communication (Hamanaka & Chandel, 2010; Ristow & Schmeisser, 2011). It becomes clear that reactive oxygen species are not necessarily always harmful (Brigelius-Flohé, 2009). A research of EGCG from green tea suggested antioxidants may be potent agents causing reductive damage (Lu, Ou, & Lu, 2013). It was observed that antioxidant consumption may neutralize any positive outcomes of exercising (Ristow et al., 2009). According to the meta-analysis of available clinical data about vitamin supplementation, the consumption of beta-carotene, vitamin A, or vitamin E has been associated with higher all-cause mortality (Bjelakovic, Nikolova, Gluud, Simonetti, & Gluud, 2012). One Danish research group found association between supplemented folic acid and increased all-cause mortality (Roswall et al., 2012). On the other hand, other researchers did not identify any effects on mortality (Henríquez-Sánchez et al., 2015) or even found the inverse association (Zhao et al., 2016; Bastide et al., 2017). It is possible that some unknown factors are in play which lead to controversy and confusion caused by so many different results.

The most well-known antioxidant is probably L-ascorbic acid, so-called vitamin C. Human body is unable to synthesize it and its absence or deficiency in diet causes fatal disease known as scurvy. However, the level of vitamin C in blood plasma is strictly regulated by organism, therefore high oral doses of L-ascorbic acid in any form do not elevate its plasma levels accordingly (Padayatty et al., 2004). There has been a lot of research done about potential effects on aging-related diseases, but the currently available evidence does not support any benefits (“Vitamin C Fact Sheet for Health Professionals,” 2016). Although, according to some researchers, there is a potential to use L-ascorbic acid intravenously in cancer treatment (Padayatty, Riordan, Hewitt, Katz, Hoffer, & Levine, 2006).

Another antioxidant which received a lot of attention is alpha-tocopherol, the only form of vitamin E with high enough biological activity to meet human requirements. Recommended daily intake is less precisely determined, compared to vitamin C. No beneficial effects were confirmed in studies with high number of participants (“Vitamin E Fact Sheet for Health Professionals,” 2016), some researchers even proposed possible harmful effects, such as increased general mortality in supplemented groups (Bjelakovic, Nikolova, Gluud, Simonetti, & Gluud, 2007).

Carotenoids also display antioxidant properties, the most popular of them is beta-carotene, sometimes called provitamin A (“Vitamin A Fact Sheet for Health Professionals,” 2016). Unfortunately, no benefits have received sufficient support by multiple studies. And it has been suggested that beta-carotene was found to increase the risk of lung cancer and cardiovascular diseases (The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study Group, 1994; Goodman et al., 2004). Another molecule from this group is lycopene, results of studies are mixed but the data from The Health Professionals Follow-up Study indicate a reduced risk of prostate cancer (Giovannucci, Liu, Platz, Stampfer, & Willett, 2007). Lutein seems to decline age-related macular degeneration (Richer et al., 2004). Astaxanthin is the strongest carotenoid antioxidant (Ursoniu, Sahebkar, Serban, & Banach, 2015) and researchers claim it has beneficial effects on humans (Cohaire, Garem, Mahmoud, Eertmans, & Schoonjans, 2005) but no large study was yet concluded.

Plant polyphenols (and their most numerous subgroup flavonoids) are abundant in nature as well as in our diet, and are generally nontoxic (Yao et al., 2004; Manach, Scalbert, Morand, Remesy, & Jimenez, 2004). In spite of these facts, they received scientific attention only for a short period of time, compared to aforementioned antioxidants. It is worth to note that recent research shows their potential benefits go often well beyond antioxidant mechanism (Scalbert, Johnson, & Saltmarsh, 2005; Kim, Quon, & Kim, 2014; Srivastava & Mishra, 2015).

The grape derived flavonoid polyphenolic substance resveratrol became widely known in anti-aging circles but shows very little bioavailability in vivo (Goldberg, Yan, & Soleas, 2003) and no lifespan extension in mammals has been conclusively shown.

Good, popular and easy-to-access source of catechins and other flavonoids is tea. According to many studies, its chemical composition provides antioxidant, anticancer, neuroprotective, cardioprotective and other beneficial health effects (Fujiki et al., 1999; Rietveld & Wiseman, 2003; Caruana & Vassallo, 2015). EGCG, or epigallocatechin-3-gallate, is a major tea polyphenol (Nagle, Ferreira, & Zhou, 2006; Singh, Shankar, & Srivastava, 2011). Interestingly, bioavailability of tea polyphenols does not change with the addition of milk (Kyle, Morrice, McNeill, & Duthie, 2007).

Curcumin, the main physiologically active polyphenol of turmeric, shows antioxidant and anti-inflammatory properties in humans (Ursoniu, Sahebkar, Serban, & Banach, 2015) and exhibits high level of safety and tolerability (Gupta, Patchva, & Aggarwal, 2013). Although, its bioavailability is very poor if taken alone, but drastically increases by about 2000% if consumed with an addition of piperine (Shoba et al., 1998). Other promising techniques of enhanced drug delivery are also being investigated (Prasad, Tyagi, & Aggarwal, 2014).

The most important antioxidant for humans is probably endogenous glutathione which is abundantly present in our cells. It scavenges free radicals very efficiently, directly regulates immune functions and levels of oxidative stress (Wu, Fang, Yang, Lupton, & Turner, 2004; Pizzorno, 2014). Furthermore, recent research conducted on humans showed that daily glutathione consumption can significantly increase its body stores (Richie et al., 2014). N-acetylcysteine supplementation boosts glutathione biosynthesis (Pendyala & Creaven, 1995).

Alpha lipoic acid (and its reduced form, dihydrolipoic acid), another interesting endogenous antioxidant, is crucial for mitochondrial functions (Palaniappan & Dai, 2007). It is also a chelator substance as it has the ability to eliminate metal ions but do not cause metal depletion in organism. Alpha lipoic acid is able to reduce the oxidized forms of vitamin C and E (Gomes & Negrato, 2014). Orally supplemented lipoic acid accumulates in tissues and evidence suggests its antioxidant properties are indirect but still beneficial (Shat, Moreau, Smith, Smith, & Hagen, 2009).

Coenzyme Q10 plays a key role in mitochondrial and other metabolic processes. It displays antioxidant properties and can be supplemented orally (Littarru & Tiano, 2007). Aging related Q10 deficiency has been linked to cardiovascular diseases (Singh, Devaraj, & Jialal, 2007). Research showed that sufficient intake can prevent or treat these issues (Kumar, Kaur, Devi, & Mohan, 2009; Mortensen et al., 2014) but another review study calls for trials with better design (Flowers, Hartley, Todkill, Stranges, & Rees, 2013).

Melatonin also participates in the protection from oxidative damage by stimulation of glutathione production (Fusco, Colloca, Lo Monaco, & Cesari, 2007). Particularly high concentrations were found in cell nucleus and mitochondria (Aydogan, Yerer, & Goktas, 2006). Melatonin is well-known as a sleep hormone and in darkness is naturally produced by brain (Peuhkuri, Sihvola, & Korpela, 2012).

Typical age-related diseases are cardiovascular, cancer, type 2 diabetes, Alzheimer’s disease (Everitt et al., 2006). Interestingly, they cause about 90 percent of deaths annually in industrialized countries (de Grey, 2007). Therefore, if antioxidants were effective in reducing these health problems, we could claim they are relevant for life extension, even if they are not relevant for the extension of maximal lifespan. However, whether or not this is the case remains controversial, especially in the case of certain vitamins (as described above). One speculation would be that the contradicting results might be explained by the non-homogeneous of vitamins among the population (Semba, 2012). Antioxidants in the diet seem to be a necessity but the benefits of dietary supplement consumption remain questionable. Some supplements contain unnecessarily high doses which do not offer any benefits but may even lead to adverse effects. On the other hand, the health impact of some polyphenolic antioxidants seems to go well beyond their basic antioxidant mechanism (Scalbert, Johnson, & Saltmarsh, 2005).

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Zhao, L., Zhang, Q., Zheng, J., Li, H., Zhang, W., Tang, W., & Xiang, Y. (2016). Dietary, circulating beta-carotene and risk of all-cause mortality: a meta-analysis from prospective studies. Scientific Reports, 6(1). http://dx.doi.org/10.1038/srep26983

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---- LongeCity comment ---
This article serves as a brief introduction into a complex and controversial topic in life extension science. For decades, anti-oxidants were almost synonymous with anti-aging. Current evidence suggests that the picture is more complex. Yet despite the potential for inefficiency and harm that antioxidants may pose, their role in modulating aging-related health cannot be ignored.
Continue the discussion of individual antioxidants in our supplements forum.

Nootropics in human trials (Intro)

Sat, 09 Sep 2017 13:57:38 +0000

The word "nootropic" derives from the Greek words nous, or "mind", and trepein meaning "to bend or turn". It was first coined by Romanian psychologist and chemist, Corneliu E. Giurgea after synthesizing Piracetam.
For Giurgea a nootropic drug should have the following characteristics:
1. They should enhance learning and memory.
2. They should enhance the resistance of learned behaviors/memories to conditions which tend to disrupt them (e.g. electroconvulsive shock, hypoxia).
3. They should protect the brain against various physical or chemical injuries (e.g. barbiturates, scopalamine).
4. They should increase the efficacy of the tonic cortical/subcortical control mechanisms.
5. They should lack the usual pharmacology of other psychotropic drugs (e.g. sedation, motor stimulation) and possess very few side effects and extremely low toxicity.

In fact, most drugs commonly labelled as nootropics do not fulfill all of these requirements. Some of the best known (e.g. Adderall, Modafinil) seem to not fulfill any, as discussed later. Instead, other characteristics like (reputed increased alertness, focus or motivation) seem to be key to their popularity.
Because of deviating definitions nootropics are more broadly defined (e.g. in wikipedia) as drugs, supplements, or other substances that improve cognitive function, particularly executive functions, memory, creativity, or motivation, in healthy individuals.

Some nootropics from the very common to the :

Caffeine
Caffeine is the world’s most widely used stimulant (Nawrot, et al., 2003). It is used by over 90 % of North Americans every day (Mednick et al., 2008). It is widely used because of its positive effects on mood and alertness (Lorist & Tops, 2003)and vigilance and attention (Lieberman et al., 1987). However, these effects do not seem applicable / transferable to motor learning and verbal memory and are unable to reverse effects of sleep deprivation, with a dose of 200mg in low to moderate users (< than 2 cups a day) (Mednick et al., 2008). It is also shown to be ineffective in higher cognitive tasks involving working memory (Battig et al., 1984). Overall conclusions regarding the relation of caffeine and memory have been mixed. Positive effects might stem from caffeine withdrawal in high dosage users (Mednick et al., 2008).

Nicotine
With about 1,1 billion smokers worldwide in the year 2015 (WHO 2015) nicotine takes second place as the most widely used stimulant. It was shown that the application of nicotine in non-smoking males enhances performance in continuous performance tasks and therefore is said to improve attention and working-memory (Kumari, et al., 2003), which is in line with other studies suggesting that nicotine affects short-term memory in delayed free recall tasks (Sarah & Fox, 1998)
Another study examined nicotine’s effects on alertness and performance on a covert orienting task were measured. While nicotine decreased overall reaction times in the covert orienting task, there was no change in the validity effect, the reaction time difference between validly and invalidly cued targets. However, nicotine significantly improved both EEG and self-rated measures of alertness. Nicotine seems to increases alertness in non-smokers, with no improvement in spatial attention using a covert orienting task (Griesar et al., 2002). Furthermore Nicotine seems to reduce distraction under low perceptual load by acting as a stimulus filter that prevents irrelevant stimuli entering awareness (Behler et al., 2015).

Methylphenidate/ Ritalin
Most college students I know will immediately think of Ritalin or Modafinil if they are asked to name a cognitive enhancer. Studies have found that 4.1% to 10.8% of college students in the US reported using prescription stimulants non-medically during the past year (Garnier-Dykstra, et al., 2012).
Methylphenidate (MPH - common brand name ‘Ritalin’) is used in treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. Most studies focused on the its effects on Attention, Mood, Memory and executive functions. A single dose of MPH showed a positive effect on memory. Repeated doses of MPH had a mood elevating effect but also enhanced anxiety. No statistically significant effect was found in the outcomes attention, mood and executive functions. MPH had no significant effect on sleep-deprived individuals (Repantis et al., 2010). In a 2015 review the authors found some ‘publication bias’, relating to long-term and working memory and conclude that the effect in healthy subject is probably modest overall and that healthy users resort to stimulants to enhance their energy and motivation more than their cognition (Ilieva et al., 2015).

Modafinil
Modafinil is used in treatment of disorders such as narcolepsy, shift work sleep disorder, and excessive daytime sleepiness associated with obstructive sleep apnea. Most studies focused on its effects on attention, mood, memory, wakefulness and executive functions and motivation. A single dose showed positive effects on attention only. On sleep deprived individuals it was shown to have an impact on executive functions, on memory and wakefulness but there was an insignificant effect on mood and attention (Repantis et al., 2010). A 2012 meta-analysis found that Modafinil was likely effective but criticised the gaps in the literature. (Kelley et al., 2012)
A recent study on chess players found significantly enhanced performance with Modafinil or Ritalin but only when the players were not under time pressure (Franke et al. 2017).

Adderall
Mixed Amphetamine Salts also known under the brand Name Adderall became increasingly popular in recent years as an athletic performance enhancer and cognitive enhancer. Like Ritalin, it is also used to treat ADHD and narcolepsy.
Overall effects of Adderall on cognition have been reviewed as very modest, while having a huge effect on perception. It was found to enhance performance in word recall, embedded figures and Raven's Progressive Matrices, but only for lower performing individuals (Ilieva et al., 2013). Adderall might also impair creativity in high performing individuals (Farah et al., 2009).

L-theanine & Caffeine
L- theanine is primarily found in plants (e.g. in the leaves of green and black tea) and fungus. Results evidently demonstrated that L-theanine clearly has a pronounced effect on attention performance and reaction time response in normal healthy subjects susceptible to having high anxiety (Higashiyama et al., 2011).
A dose of L-theanine equivalent to eight cups of black tea improves cognitive and neurophysiological measures of selective attention, to a degree that is comparable with that of caffeine. The combination of Theanine and caffeine seem to have additive effects on attention in high doses (Kahathuduwa et al.,2016).
Studies suggest that 97 mg of L-theanine in combination with 40 mg of caffeine helps to focus attention during a demanding cognitive task (Giesbrecht 2010).

Bacopa Monnieri
Bacopa Monnieri is an herb which has been used in Ayurvedic medicine for centuries. Bacopa's primary mechanism of action is still unclear, it seems to be an anti-oxidant, a weak acetylcholinesterase inhibitor and a cerebral blood flow activator (Aguiar & Borowski , 2013).
There is some evidence to suggest that Bacopa Monnieri improves memory with little evidence of enhancement in any other cognitive domains (Pase et al., 2012).

Piracetam
Closing the circle to the beginning of this short introduction to the topic: Giurgea first coined the term "nootropic" when he synthesized Piracetam in 1964. Since it is not approved by the US FDA, it is primarily used in Europe, Asia, and South America. It is commonly prescribed for cognitive impairment and dementia in several countries of Europe. Research suggests that Piracetam might also have a positive effect on healthy individuals. Subjects were given 3×4 capsules at 400 mg per day, in a double blind study. Each subject learned series of words presented as stimuli upon a memory drum. No effects were observed after 7 days but after 14 days verbal learning had significantly increased (Dimond & Brouwers, 1976). It might also be beneficial for cognitive decline associated with age. Aging subjects did significantly better in a computerized perceptual-motor tasks when on piracetam than on a placebo. (Mindus et al. 1976). While these old studies may not be that reliable, it is still held that Piracetam's “efficacy is documented in cognitive disorders and dementia, vertigo, cortical myoclonus, dyslexia, and sickle cell anemia. While high doses are sometimes necessary, piracetam is well tolerated” (Winblad, 2005). Since Piracetam was first synthesized many structurally similar compounds have emerged. These so called Racetams have poorly understood mechanisms of action; however, piracetam and aniracetam are known to act as positive allosteric modulators of AMPA receptors and appear to modulate cholinergic systems (Gualtieri et al., 2002).

This article is solely for information purposes, not a substitute for professional medical or dietary advice.
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References
* Aguiar, S., & Borowski , T. (2013). Neuropharmacological review of the nootropic herb Bacopa monnieri. Rejuvenation Research, 313-326.
* Battig , K., Martin, J. R., & Feierabend , J. M. (1984). The effects of caffeine on physiological functions and mental performance. Experentia, 1218–1223.
* Behler , O., Breckel, T. P., & Thiel , C. M. (2015). Nicotine reduces distraction under low perceptual load. Psychopharmacology, 1269-1277.
* Dimond, S. J., & Brouwers, E. M. (1976). Increase in the power of human memory in normal man through the use of drugs. Psychopharmacology, 307-309.
* Farah , M., Haimm , C., Sankoorikal , G., Smith , M., & Chatterjee , A. (2009). When we enhance cognition with Adderall, do we sacrifice creativity? A preliminary study. Psychopharmacology,541-547.
* Franke, A.G.; Gränsmark, P., Agricola, A., Schühle, K., Rommel, T., Sebastian, A., Balló, H.E., Gorbulev, S., Gerdes, C., Frank, B., Ruckes, C., Tüscher, O., Lieb, K. (2017) "Methylphenidate, modafinil, and caffeine for cognitive enhancement in chess: A double-blind, randomised controlled trial" in: European Neuropsychopharmacology Vol27, Issue 3, 1, pp248-260
* Garnier-Dykstra, L. M., Caldeira, K. M., Vincent, K. B., O’Grady, K. E., & Arria, A. M. (2012).Nonmedical use of prescription stimulants during college: Four-year trends in exposure opportunity, use, motives, and sources. J Am Coll Health, 226-234.
* Giesbrecht, T., Rycroft , J. A., Rowson , M. J., & De Bruin , E. A. (2010). The combination of L-theanine and caffeine improves cognitive performance and increases subjective alertness. Nutritional Neuroscience, 283-290.
* Griesar , W. S., Zajdel , D. P., & Oken , B. (2002). Nicotine effects on alertness and spatial attention in non-smokers. Nicotine & Tobacco Research, 185-194.
* Gualtieri , F., Manetti , D., Romanelli , M. N., & Ghelardini , C. (2002). Design and study of piracetamlike nootropics, controversial members of the problematic class of cognition-enhancing drugs. Current Pharmaceutical Design, 125-138.
* Higashiyama, A., Htay, H. H., Ozeki, M., Juneja, L. R., & Kapoor, M. P. (2011). Effects of l-theanine on attention and reaction time response. Journal of Functional Foods, 171-178.
* Ilieva, I., Boland, J., & Farah, M. (2013). Objective and subjective cognitive enhancing effects of mixed amphetamine salts in healthy people. Neuropharmacology, 496-505.
* Ilieva IP, Hook CJ, Farah MJ. (2015) Prescription Stimulants' Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis.; J Cogn Neurosci. 2015 Jun;27(6):1069-89.
* Kahathuduwa, C. N., Dassanayake , T. L., Amarakoon , A. M., & Weerasinghe, V. S. (2016). Acute effects of theanine, caffeine and theanine-caffeine combination on attention. Nutritional Neuroscience.
* Kelley, A.M.; Webb, C.M., Athy, J.R., Ley, S., Gaydos, S. (2012) "Cognition enhancement by modafinil: A meta-analysis" in Aviation Space and Environmental Medicine; Vol83, Issue 7, p685-690
* Kumari, V., Gray, J., H ffytche, D., Mitterschiffthaler, M., Das, M., Zachariah, E., . . . Sharma, T. (2003). Cognitive effects of nicotine in humans: an fMRI study. NeuroImage, 1002-1013.
* Lieberman , H. R., Wurtman, R. J., Emde, G. G., Roberts , C., & Coviella, I. L. (1987). The effects of low doses of caffeine on human performance and mood. Psychopharmacology, 308-312.
* Lorist , M. M., & Tops, M. (2003). Caffeine, fatigue, and cognition. Brain Cognition, 82-94.
* Mednick, S. C., Cai, D. J., Kanady, J., & Drummond, S. P. (2008). Comparing the benefits of Caffeine,Naps and Placebo on Verbal, Motor and Perceptual Memory. Behavioural Brain Research, 79–86.
* Mindus , P., Cronholm , B., Levander , S. E., & Schalling , D. (1976). Piracetam-induced improvement of mental performance. A controlled study on normally aging individuals. Acta Psychiatrica Scandinavia, 150-160.
* Nawrot, P., Jordan, S., Eastwood , J., Rotstein , J., Hugenholtz, A., & Feeley, M. (2003). Effects of caffeine on human health. Food Additives & Contaminants, 1-30.
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* Repantis , D., Schlattmann , P., Laisney , O., & Heuser, I. (2010). Modafinil and methylphenidate for neuroenhancement in healthy individuals: A systematic review. Pharmacological Research, 187-206.
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Aging theories: Is there a unifying factor in a...

Sun, 20 Aug 2017 18:04:47 +0000

When Darwin’s theory of evolution by natural selection was established, biologists were puzzled by the existence of senescence and aging among all organisms. Why did the evolutionary pressure not produce immortal species? They concluded that even the power of evolution has its limitations. It took almost hundred years to reach the idea that mortal individuals may be preferred by nature for following reasons — the genes resulting in advantage in early life might cause damage in late life, and the reproduction starts as soon as possible. Around the middle of twentieth century, there finally was a framework for the gerontological research conduced in the following decades — the first evolutionary theories of aging (Gavrilov & Gavrilova, 2002).
There are two major groups of theories aiming to explain the mechanism of aging, so-called programmed and error theories. The programmed ones are based on the senescence-causing nature of certain genes (these are also called evolutionary theories), hormones or the immune system. Error theories claim that we age because of general damage caused by cell weariness, metabolic rate, cross-linked proteins, free radicals or somatic DNA changes (Jin, 2010).
The beauty of various aging theories is that most of them are not mutually exclusive. We can see that newer theories do not necessarily oppose the old ones, but rather shed more light and offer more in-depth views on the process of senescence.
The pioneering idea from 1882 was Weismanns’s theory of programmed death (also called wear-and-tear theory) claiming something like apoptosis of the multicellular organism. Although disproved by experiments, his theoretical explanation of the mechanism predicted the discovery of Hayflick limit (Gavrilov & Gavrilova, 2002). According to Weismann’s first conception, nature priorities young individuals over elderly because of limited resources. Pearl stated his ‘rate of living’ theory of aging in 1928, although the idea comes from Rubner who, in 1908, suggested that every organism has limited amount of metabolic energy and therefore its age depends on the rate of metabolism which correlates with organism’s size (Pearl, 1928). Most consider the rate of living theory to be flawed (Lints, 1989; de Magalhaes, Costa, & Church, 2007; Vaanholt, Daan, Schubert, & Visser, 2009).
A few decades later, the following evolutionary models have emerged: Medawar’s hypothesis of mutation accumulation proposes that aging is a by-product of natural selection — genes causing senescence in later stadium of life cannot be eliminated because the genetic information was most likely already transferred to successors by individuals in their early adulthood (Gavrilov & Gavrilova, 2002). This theory from 1952 is considered the first modern theory of aging. Charlesworth confronted Medawar’s model with a discovery of late-life mortality plateaus and in 1994 presented so-called modified mutation accumulation theory (Charlesworth, 2001; Ljubuncic & Reznick, 2009). In his antagonistic pleiotropy theory (also called ‘pay later’ theory), Williams in 1957 expressed the idea that even the same genes which cause trouble at advanced age may be advantageous in earlier stages of life, and therefore be not only tolerated, but even preferred by natural selection (Gavrilov & Gavrilova, 2002). In 1979, Kirkwood extended this theory to the disposable soma theory — organisms may save energy by reducing accuracy in cells metabolism and invest it in faster development and reproduction (Kirkwood & Holliday, 1979). This is the last one of famous, genes-orientated evolutionary models.
The following can be classified as programmed theories: The neuroendocrine theory proposed in 1954 by Dilman says that the main cause of aging is a loss of receptor sensitivity of the hypothalamus over time, and therefore its control of adequate production of hormones declines which leads to ineffectiveness and lower hormone levels in organism. It is an attempt to explain a high occurrence of degenerative diseases in late age (“Neuroendocrine Theory of Aging: Chapter 1,” 1999). Research on hormonal signaling pathways confirms that hormone levels have at least a partial role in determining longevity (van Heemst et al., 2005). In 1964, Walford suggested his immunologic theory of aging — due to increasing diversity of cells, the immune system looses its efficiency with age which leads to insufficient responses against pathogens as well as to autoimmune reactions against self proteins (Walford, 1964).
All following attempts to explain the mechanism behind a process of aging are usually called error or damage theories. Bjorksten’s "crosslinkage theory" says that proteins become linked together in presence of certain crosslinking agents, and after some time, accumulation of these molecular aggregates causes decline in tissue functions. This theory from 1942 is no longer popular (Bjorksten, 1968). Later research has showed that advanced glycation end products (AGEs) accumulate in collagen and lead to outcomes predicted by Bjorksten (Verzijl et al., 2002; Aronson, 2003).
These days very popular among researchers and public, the free radical theory was suggested by Harman in 1956. His idea was that the occurrence of free radicals, or reactive oxygen species naturally produced in living organisms, leads to macromolecular damage which accumulates and causes physiological changes known as senescence (Harman, 2009). Later he suggested the reactive oxygen species formation takes place mainly in mitochondria which causes a decline in important mitochondrial functions (Harman, 1972). Because of the theory’s popularity, various extensions of Harman’s model were created, usually considering different sites as a main target of free radicals.
Failla’s somatic mutation theory from 1958 posits that increasing number of mutations of genetic material causes a decrease in cellular, organ and body functions (Failla, 1958; Gensler & Bernstein, 1981; Kennedy, Loeb, & Herr, 2012). The theory received a lot of criticism in previous decades (Vijg, 2000). Kaya, Lobanov and Gladyshev (2015) investigated aging in yeast and failed to find evidence in support of Failla’s thesis.
Orgel proposed his error catastrophe theory in 1963. He saw the cause of aging in accumulation of malfunctioning proteins coming from errors during protein translation (Orgel, 1963). This theory never gained popularity and was soon disproved (Gershon & Gershon, 1976).
Alexander in 1967 extended Failla’s theory by hypothesizing that DNA damage instead of mutation is the cause of aging (Alexander, 1967). These days, this version called "somatic DNA damage theory of aging" is more often used by scientists (Freitas & de Magalhaes, 2011; Soares et al., 2014). Evidence suggests that more damage happens in mitochondrial DNA than in nuclear DNA (Ames, 2009).
In 2002, Brunk and Terman published the mitochondrial-lysosomal axis theory. It states that defective macromolecules derived from mitochondria undergo further changes in lysosomes to become lipofuscin inclusions. These end products decrease cell’s autophagocytotic capacity which leads to more mitochondrial defects (Brunk & Terman, 2002).
Zs.-Nagy’s "membrane hypothesis" focuses on a decline of mitochondrial functions due to lessened membrane permeability caused by residual heat coming from nerve signals as well as by reactive oxygen species (Zs.-Nagy, 2014).
Recent versions of damage theories claim that free radicals are only one kind of senescence-causing by products of metabolism but the real initiator of all the inevitable damage is biological imperfectness. In other words, there are always types of damage which lack adequate repair mechanisms in organism and the most severe source of errors depends on actual conditions (Gladyshev, 2013; Gladyshev, 2014). This idea comes from the "reliability theory", which focuses on systems failure in machines (Gavrilov & Gavrilova, 2001). In spite of many research programs and lots of scientists involved, the unifying factor in aging is at the moment still unknown.

References

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Vijg, J. (2000). Somatic mutations and aging: a re-evaluation. Mutation Research/Fundamental And Molecular Mechanisms Of Mutagenesis, 447(1), 117-135. http://dx.doi.org/10.1016/s0027-5107(99)00202-x
Walford, R. (1964). The Immunologic Theory of Aging. The Gerontologist, 4(4), 195-197. http://dx.doi.org/10.1093/geront/4.4.195
Zs.-Nagy, I. (2014). Aging of Cell Membranes: Facts and Theories. Aging, 62-85. http://dx.doi.org/10.1159/000358900

The above is a short perspective by Vit Zemanek. Continue the discussion and analysis on LongeCity's long-running AGING THEORIES forum.

Geroprotector Review: Rapamycin and other mTOR...

Tue, 18 Jul 2017 21:03:16 +0000

Sven Bulterijs continues his discussion of prominent compounds with potential life extension efficacy by looking not just at rapamycin but also at its target, the mTOR pathway, which has likely a key role in mediating lifespan. ⇒ read the article in "Sven's Science Corner" blog

Metformin - a geroprotector?

Fri, 19 May 2017 19:12:06 +0000

Sven Bulterijs first discussed the potential utility of anti-diabetic substance metformin six years ago on LongeCity. Now Sven returns to the topic with a comprehensive and thoughtful discussion of the recent findings and further background information ⇒ read the article in "Sven's Science Corner" blog

Aschwin de Wolf: Cryonics

Sun, 19 Feb 2017 13:12:14 +0000

Interview with Aschwin de Wolf (February, 2017)

Aschwin de Wolf is the CEO of Advanced Neural Biosciences, a neural cryobiology research company in Portland, Oregon. Originally from the Netherlands, Aschwin has extensive knowledge as a writer, researcher, consultant and in project management. He worked as the CFO for Suspended Animation Inc., is a co-founder of the Institute for Evidence-Based Cryonics, and edits Alcor’s 'Cryonics' magazine.

The interview was conducted by Sven Bulterijs

1. How has the cryopreservation procedure evolved since the first human was placed in cryostasis?

AdW: The most important element in the progress of cryopreservation procedures in cryonics is the progressive elimination of ice formation. When cryonics started, patients were often cryopreserved without any cryoprotection or very low concentrations of cryoprotectant. In the 1980’s and 1990’s organizations such as Alcor started adapting mainstream perfusion technologies to introduce high concentrations of cryoprotectants (such as glycerol) to mitigate ice formation. In 2000 Alcor formally introduced vitrification with the aim of eliminating freezing altogether.

2. Have changes in the procedure over the last decades (composition of cryoprotectant, rate of cooling, etc.) lead to a measurable decrease in the damage that occurs during vitrification?

AdW: Yes. The elimination of ice formation, which can be achieved in good cases, removes one major form of mechanical damage in the cryopreserved brain. One very attractive feature of a low-toxicity vitrification agent like M22 is that it does not require rapid cooling to prevent ice formation. Under good circumstances (no prior ischemia) it can also be used in whole-body patients without edema – a problem that seemed to plague prior DMSO-based cryoprotectants in cryonics. Elimination of ice formation and reduced toxicity has substantially reduced the degree of damage associated with cryopreservation.

3. Which foreseeable advances in the field of cryobiology do you believe will lead to improvements in cryonics?

AdW: I foresee further advances in two areas; a more detailed understanding of the nature of cryoprotectant toxicity and the design of brain-optimized cryoprotectants. Cryoprotectant toxicity is currently the most formidable obstacle preventing reversible cryopreservation of complex mammalian organs. With the exception of the work of Dr. Greg Fahy and his colleagues at 21^st Century Medicine, it is rather surprising how little theoretical and experimental research has been done to illuminate the mechanisms of cryoprotectant toxicity. It is also increasingly recognized that the poor penetration of cryoprotectants across the blood-brain barrier causes dehydration of the brain. We need to develop brain-optimized vitrification solutions and/or identify better methods to deliver cryoprotectants to the brain without such significant changes in brain volume. Resolving these two issues will bring us much closer to reversible brain cryopreservation.

4. People have experimented in the past with a wide variety of antioxidants, chelators and membrane stabilizing molecules to reduce the damage to the body at the start of the procedure (so just after legal pronunciation of death). Have any of these been successful and are people still trying to find such substances to reduce damage at the early moments of the procedure?

AdW: I think it is important to recognize that all these anti-ischemia interventions are more important when there is a delay between pronouncement of death and the start of cryonics procedures. If there is a rapid and smooth transition between the two, immediate restoration of circulation, rapid induction of hypothermia, and aggressive anti-thrombotic therapy should be sufficient to maintain cerebral viability of the brain by contemporary medical criteria.

Our lab Advanced Neural Biosciences, has collaborated with Alcor to conduct a rather comprehensive study of the effects of Alcor’s stabilization medications protocol and the most robust finding in this research has been that the combination of heparin and citrate allows for ice-free cryopreservation of the brain when these compounds are administered immediately after pronouncement of legal death. When medication administration is delayed by more than 15 minutes, things get more challenging and breakdown of the blood brain barrier and whole-body edema during cryoprotective perfusion is a typical outcome. Preventing edema of the patient during cryoprotective perfusion after prolonged periods of ischemia remains one of the most difficult research challenges to solve.

5. What evidence is there that the brain is not damaged by the cryopreservation process to such an extent that the information in it may be lost forever?

AdW: I can answer this in two ways. To start with, if we can eliminate ice formation in the brain, the damage associated with cryoprotectant toxicity is assumed to be mostly of a biochemical nature (i.e. denatured proteins) and does not alter the ultrastructure of the brain in a way that precludes inferring the original state. Cryoprotectant-induced dehydration of the brain is a little more of a wild card because we do not have much detailed information about the kind of ultrastructural changes associated with it. Hence, the priority to avoid the brain shrinking that is routinely observed in “good” cases. Ultimately, our incomplete knowledge of the neuroanatomical basis of identity, and about the exact capabilities and limits of future medicine, prompt us to be agnostic about the degree of damage that is still compatible with meaningful revival. Advocates of cryonics are sometimes accused of being too optimistic about future science, but perhaps skeptics are too pessimistic.

6. Do any changes take place in the bodies during cryogenic storage? And if such changes take place does that mean that the chance on successful reanimation will decrease over time?

AdW: No. To our knowledge (which is based on cryobiological studies and theoretical calculations), deterioration of patients stored at cryogenic temperatures should be non-existent or negligible. Things get a little bit more complicated when we store patients at intermediate temperatures (intermediate temperature storage or “ITS”) instead of liquid nitrogen temperatures. It has been suggested that nucleation may still occur slightly below the temperature where the vitrification solution turns into a glass (-123 degrees Celsius). At that temperature, however, nucleation does not translate into ice formation but it might create more challenging repair and revival scenarios.

7. Do you have any hypotheses on how the cryoprotectant could be removed from the body during the reanimation procedure and how hypoxic injury during this removal procedure could be prevented?

AdW: Roughly speaking, there are two distinct approaches to the repair and revival of cryonics patients. In the vision of researchers such as Robert Freitas and Ralph Merkle, a mature form of mechanical nanotechnology will be used to conduct the initial stages of repair and cryoprotectant removal at cryogenic temperatures. If this vision of nanotechnology is plausible, cryoprotectant can be removed while providing (local) metabolic and structural support to prevent damage or freezing. An alternative vision of nanomedicine will involve the use of biological repair machines such as modified viruses or modified white blood cells that operate using conventional diffusion-driven chemistry rather than molecular mechanical nanotechnology. Repair is more challenging in this biological scenario because tissue first needs to be warmed to temperatures at which the cryoprotectant solution inside cells and tissue becomes liquid. This risks movement of damaged structures, possible growth of ice, and cryoprotectant toxicity accumulation occurring at the same time as repairs are being made. To my knowledge, there have not been many serious studies of how such devices can operate and navigate through these problems at the same time.

8. What is in your opinion the chance that a cryopreserved person would be revived in a human state versus an uploaded version as uploading may be a way around irreparable cryopreservation damage?

AdW: I am personally partial to the idea of doing molecular level repairs through mechanical or biological nanomedicine because it does not require a paradigm shift in how we think about the nature of identity and consciousness. The feasibility of mind uploading is ultimately about the feasibility of substrate-independent minds and I do not think that the debates surrounding this can be resolved prior to empirical verification. In my opinion, the proposal of cryonics is intrinsically linked to the idea that the non-damaged state of the brain can be inferred from the damaged state through some form of molecular medicine. Many people feel quite comfortable with reconstruction of ancient DNA or forensic inference, but when it comes to cryonics, people tend to treat the brain in a somewhat superstitious fashion and cannot imagine forms of medicine that operate with molecular precision.

9. Even if reanimation after cryopreservation becomes technologically possible, what would make you believe that future generations will spend the money and resources on reanimating all people from cryostasis rather than just one or a few as an experiment?

AdW: This is an easier question to answer because it is the aim of cryonics organizations themselves to resuscitate their patients, not the general public, or curious scientists. The Alcor Life Extension Foundation parks a rather substantial portion of the cryopreservation fees in a so-called Patient Care Trust that should permit patients to be maintained in perpetuity (in theory) and revived when the technologies are available and affordable. Of course, if the technologies to revive cryonics patients will come to fruition, it seems quite reasonable to assume that the legal status of cryonics patients will also change and patients at cryonics organizations will be considered living people in a critical condition.

10. Do you see a mutual exchange of techniques and knowledge between the human cryopreservation field and the field of storing human biological samples (e.g. sperm, fertilized eggs, etc.)?

AdW: Yes. As a general rule, the obstacles that are faced by researchers of storage of biological samples and complex mammalian organs are the same obstacles that need to be overcome for reversible cryopreservation of humans (medical biostasis) as well. Any insights into the mechanisms of cryoprotectant toxicity, chilling injury, and the effects of cryopreservation on gene expression are of great relevance to cryonics. I should add, however, that I expect this exchange to be mutually beneficial. One of the least recognized and appreciated aspects about the field of cryonics is that researchers sympathetic to the idea of human cryopreservation have made meaningful and innovative contributions to mainstream fields such as cryobiology and cerebral resuscitation.

11. Cryogenic storage of genetic mutants in laboratory animals could reduce the cost of biomedical research. This is already a common procedure in the roundworm C. elegans. Are you aware of any research taking place that tries to expand cryogenic storage to other model organisms?

AdW: Natasha Vita-More, who conducted recent studies on the effects of vitrification on memory in C. elegans, has suggested that the next step would be a slightly more complex organism such as the Greenland Woolly Bear Caterpillar or the ozobranchid leech. One of the most common suggestions I get is to attempt suspended animation on a mouse or rat. This would definitely provide powerful proof of principle for the feasibility of human suspended animation, but I do not think that the challenges in achieving reversible biostasis in a small mammal are that much smaller than in humans. We would need to overcome the same obstacles: minimizing cryoprotectant toxicity, chilling injury, dehydration of the brain, ischemia during cooling, and cryoprotective perfusion, etc. The majority opinion in cryonics is to solve these individual problems more thoroughly before attempting reversible cryopreservation of a complete animal.

12. In a recent ruling on a 14-year old girl wanting cryonics, a UK judge stated that there is a lack of regulation concerning cryonics. If a government would ask your advice on creating such regulations then what would you tell them?

AdW: I think the first thing I would recommend is that experts (which should include researchers and practitioners of the field) create a protocol to conduct cryonics as a hospital-based, elective, medical procedure. Reviewing the technical requirements and supporting evidence for cryonics will lead to a greater recognition of the need of improved legal protection for cryonics patients. Too often, cryonics is dismissed because people do not understand the conceptual arguments in favor of it, or its multi-disciplinary nature. In particular, the idea of molecular medicine is usually ignored in discussions about the (potential) damage of cryonics procedures. If regulations and protocols are created based on a dispassionate examination of the arguments and evidence in favor of cryonics, I think we do not necessarily need to fear regulation of the field.

Why do some turtles outlive humans?

Thu, 09 Feb 2017 00:45:06 +0000

(⇒ write for LongeCity )

The oldest human recorded in modernity was Jeanne Louise Calment, she died in the age of 122 years and 164 days [1] .

There are rumors that the oldest tortoise called Adwaita (Aldabra giant tortoise) died in the age of about 250 years [2] or that it was 188-year-old radiated tortoise named Tui Malila [3] , or that the highest verified age of 177 years had Galapagos giant tortoise Harriet [4] . The oldest currently living turtle is considered to be Jonathan (Seychelles giant tortoise), estimated to be over 180 years old these days [5] . Although all aforementioned numbers are estimations, it seems these turtles were older than human supercentenarians.

All previously mentioned species are terrestrial tortoises, a group with longest lifespans among turtles. The most famous of them, well-researched Galapagos giant tortoise, was observed by Charles Darwin when he was forming his well-known theory of evolution by natural selection [6] . There is only one freshwater turtle known to be able to outlive human, it is the common snapping turtle estimated to live up to more than hundred years [7] . While being considerably less researched, recorded maximal lifespan of sea turtles is usually shorter, not exceeding 80 years, however, it is believed that the green sea turtle can live up to 100 years. [8]

It is a difficult question to answer why these reptiles can outlive us because even to determine the actual age of animals with a long lifespan is complicated – partially due to the fact that it takes such a long time to study. Furthermore, many turtles are endangered species [9] so there may not be as many organisms to hand as needed for proper statistics. Nonetheless, we can still claim that turtles are among the most long-living vertebrates on earth [10] . Why?

Firstly, turtles, like all reptiles, benefit from being ectothermic organisms. They do not maintain body temperature and thus save a lot of energy. But that also means they are less flexible: it is crucial for their lifespan to be in natural temperature environment of daily cycles with night-time temperature drop [11] . If they do not live under these conditions in captivity, metabolic pathways change and turtles die much sooner. [12]

Turtles are well-adapted in other ways: their famous shell – the carapace –is good protection against natural predators. Most of hatchling turtles with a soft shell do not survive the first year [13] . A research of natural populations of freshwater turtles showed that only one per cent of them can celebrate the twentieth birthdays, but once the adulthood is reached, mortality rate drops and remains constant throughout the rest of life [14] .

Some turtles can survive under extreme environmental conditions, such as freezing [15] or lack of oxygen for months [16] . They can even undergo hibernation and anaerobic metabolism and therefore deal with hypoxia and anoxia, it was also proposed that the same genes can play a role in longevity itself [17] and also in oxidative stress resistance [18] that further promotes longer life [19] .

Turtle’s bones and shell are used as lactate buffer lowering metabolic acidosis caused by anaerobic glycolysis during the period of lack of oxygen [20] ; [21] Their organism is protected by strong innate immunity compensating slow acquired immune reactions [22] .

Because turtles have very slow metabolism as well as growth, their bodies do not need to deal with excessive metabolic heat and byproducts as mammals [23] . Their natural diet is very simple but also necessary for their longevity. [24]

According to the evolutionary theories, staying alive is less important after menopause. Galapagos giant tortoises achieve sexual maturity late (around the age of up to forty years in the wild, and between twenty and twenty-five years of life in captivity [25] ), then staying fertile until death [26] .

The Hayflick limit is said to determine how many times a cell can divide [27] . The Hayflick limit of Galapagos giant tortoise was said to be about 110 divisions [28] , approximately twice as many as 50 of human cells [29] . Studies in this context have highlighted the importance of telomeres, the protective end sequences of chromosomes, that get shorter with each cell division [30] , can play at least a partially role in life expectancy. It was observed that telomeres in European freshwater turtle’s cells are of the same length in both embryo and adult organism [31] .

Thus, it was believed that turtles are negligibly senescent organisms [32] . In other words, the cells do not age and no age-related diseases appear, which is very different cell behavior than in human bodies [33] and probably the key to any natural longevity. However, evidence now suggests that turtles may not be really negligibly senescent because of observations of survival and reproductive senescence in late age in the painted turtle population [34]

As we can see, turtles have some advantages in the lifespan field. Some of these might inspire researchers to increase lifespans in humans.

References

[1] Oldest person ever. Retrieved January 31, 2017, from http://www.guinnessworldrecords.com/world-records/oldest-person

[2] BBC (2006, March 23). “Clive of India’s” tortoise dies. BBC South Asia. Retrieved from http://news.bbc.co.uk/2/hi/south_asia/4837988.stm

[3] Associated Press (2006, June 26). Tortoise believed to have been owned by Darwin Dies at 176. Fox News. Retrieved from http://www.foxnews.com/story/2006/06/26/tortoise-believed-to-have-been-owned-by-darwin-dies-at-176.html

[4] Galapagos tortoise (Geochelone nigra) longevity, ageing, and life history. Retrieved January 31, 2017, from http://genomics.senescence.info/species/entry.php?species=Geochelone_nigra

[5] Hollins, J. (2012). The world’s most isolated vet? Veterinary Record, 171(2), i–i. doi:10.1136/vr.g7292

[6] Powell, J., & Caccone, A. (2006). Giant tortoises. Current Biology, 16(5), R144–R145. doi:10.1016/j.cub.2006.02.050

[7] Cameron, M. (2008). COSEWIC Assessment and Status Report on the Snapping Turtle Chelydra serpentina in Canada . Retrieved from http://publications.gc.ca/collections/collection_2009/ec/CW69-14-565-2009E.pdf

[8] Green sea turtle (Chelonia mydas) longevity, ageing, and life history. Retrieved January 31, 2017, from http://genomics.senescence.info/species/entry.php?species=Chelonia_mydas

[9] Jacobson, E. R. (1994). Causes of Mortality and Diseases in Tortoises: A Review. Journal of Zoo and Wildlife Medicine, 25(1), 2–17.

[10] Gibbons, J. W. (1987). Why do turtles live so long? BioScience, 37(4), 262–269. doi:10.2307/1310589

[11] Flouris, A. D., & Piantoni, C. (2014). Links between thermoregulation and aging in endotherms and ectotherms. Temperature, 2(1), 73–85. doi:10.4161/23328940.2014.989793

[12] Vadala, N. How Long Do Turtles Live? Retrieved January 31, 2017, from http://www.petmd.com/reptile/care/how-long-do-turtles-live

[13] Stewart, K. R., & Wyneken, J. (2004). Predation risk to loggerhead hatchlings at a high-density nesting beach in Southeast Florida. Bulletin of Marine Science, 74(2), 325–335.

[14] Gibbons, J. W., & Semlitsch, R. D. (1982). Survivorship and longevity of a long-lived vertebrate species: How long do turtles live? The Journal of Animal Ecology, 51(2), 523. doi:10.2307/3981

[15] Packard, G. C., & Packard, M. J. (2003). Natural freeze-tolerance in hatchling painted turtles? Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology, 134(2), 233–246. doi:10.1016/s1095-6433(02)00264-7

[16] Milton, S. L., & Prentice, H. M. (2007). Beyond anoxia: The physiology of metabolic downregulation and recovery in the anoxia-tolerant turtle. Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology, 147(2), 277–290. doi:10.1016/j.cbpa.2006.08.041

[17] Shaffer, H. B., Minx, P., Warren, D. E., Shedlock, A. M., Thomson, R. C., Valenzuela, N., … Wilson, R. K. (2013). The western painted turtle genome, a model for the evolution of extreme physiological adaptations in a slowly evolving lineage. Genome Biology, 14(3), R28.doi:10.1186/gb-2013-14-3-r28

[18] Garbarino, V. R., Orr, M. E., Rodriguez, K. A., & Buffenstein, R. (2015). Mechanisms of oxidative stress resistance in the brain: Lessons learned from hypoxia tolerant extremophilic vertebrates. Archives of Biochemistry and Biophysics, 576, 8–16. doi:10.1016/j.abb.2015.01.029

[19] von Zglinicki, T. (2002). Oxidative stress shortens telomeres. Trends in Biochemical Sciences, 27(7), 339–344. doi:10.1016/s0968-0004(02)02110-2

[20] Jackson, D. C. (2000). Living without oxygen: Lessons from the freshwater turtle. Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology, 125(3), 299–315. doi:10.1016/s1095-6433(00)00160-4

[21] Krivoruchko & Storey, 2010).

[22] Sandmeier, F. C., Tracy, C. R., Dupre, S., & Hunter, K. (2012). A trade-off between natural and acquired antibody production in a reptile: Implications for long-term resistance to disease. Biology Open, 1(11), 1078–1082. doi:10.1242/bio.20122527

[23] Bilinski, T., Paszkiewicz, T., & Zadrag-Tecza, R. (2015). Energy excess is the main cause of accelerated aging of mammals. Oncotarget, 6(15), 12909–12919. doi:10.18632/oncotarget.4271

[24] Casares, M., Honegger, R. E., & Rubel, A. (1995). Management of giant tortoises Geochelone elephantopus and Geochelone gigantean at Zurich Zoological gardens. International Zoo Yearbook, 34(1), 135–143. doi:10.1111/j.1748-1090.1995.tb00671.x

[25] Global, S. D. Z. (2010). Galapagos tortoise fact sheet. Retrieved January 31, 2017, from http://library.sandiegozoo.org/factsheets/galapagos_tortoise/tortoise.htm

[26] Curtin, A. J., Zug, G. R., & Spotila, J. R. (2009). Longevity and growth strategies of the desert tortoise (Gopherus agassizii) in two American deserts. Journal of Arid Environments, 73(4-5), 463–471. doi:10.1016/j.jaridenv.2008.11.011

[27] Hayflick, L. (1965). The limited in vitro lifetime of human diploid cell strains. Experimental Cell Research, 37(3), 614–636. doi:10.1016/0014-4827(65)90211-9

[28] Goldstein, S. (1974). Aging in vitro. Experimental Cell Research, 83(2), 297–302. doi:10.1016/0014-4827(74)90342-5

[29] Hayflick, L., & Moorhead, P. S. (1961). The serial cultivation of human diploid cell strains. Experimental Cell Research, 25(3), 585–621. doi:10.1016/0014-4827(61)90192-6

[30] Harley, C. B., Futcher, A. B., & Greider, C. W. (1990). Telomeres shorten during ageing of human fibroblasts. Nature, 345(6274), 458–460. doi:10.1038/345458a0

[31] Girondot, M., & Garcia, J. (1999). Senescence and longevity in turtles: What telomeres tell us. 9th extraordinary meeting of the societas Europaea Herpetologica, 1, 25–29. Retrieved from //www.researchgate.net/publication/252290006_Senescence_and_longevity_in_turtles_What_telomeres_tell_us

[32] Miller, J. K. (2001). Escaping senescence: Demographic data from the three-toed box turtle (Terrapene carolina triunguis). Experimental Gerontology, 36(4-6), 829–832. doi:10.1016/s0531-5565(00)00243-6

[33] Schächter, F., Cohen, D., & Kirkwood, T. (1993). Prospects for the genetics of human longevity. Human Genetics, 91(6), . doi:10.1007/bf00205074

[34] Warner, D. A., Miller, D. A. W., Bronikowski, A. M., & Janzen, F. J. (2016). Decades of field data reveal that turtles senesce in the wild. Proceedings of the National Academy of Sciences, 113(23), 6502–6507. doi:10.1073/pnas.1600035113

Article: Gut microbiome in health and aging

Tue, 10 Jan 2017 18:01:50 +0000

As part of his new column "Sven's Science Corner" Sven Bulterijs discusses novel insights into the crucial role gut bacteria seem to play in health, disease and aging. ⇒ read the article in "Sven's Science Corner" blog

Supplement Review: Nicotinamide Riboside

Sat, 19 Nov 2016 10:04:10 +0000

review: LongeCity Crowdsourced Initiatives

Tue, 19 Jul 2016 03:34:49 +0000

'Crowdsourcing' information is at the heart of how LongeCity operates.
Consequently, almost all of Longecity's initiatives are community-led.
Some examples of projects we have crowdsourced in the past:

	BOOK: The Scientific Conquest of Death: Essays on Infinite Lifespans [2004] Commissioned and edited by the LongeCity community, this book brings together perspectives from scientists, doctors and philosophers to share their perspective on Longecity’s mission..
FILM: Exploring Life Extension [2005] Featuring an introduction into the scope on Longecity’s mission, through interviews with scientists and philosophers, this feature length documentary was entirely produced, filmed and edited by LongeCity volunteers.
	Cryonics Hardship Charity [2008, 2010] The LongeCity community supported dying individuals who were unable to afford a cryonic suspension as last resort.
Crowdsourced PRODUCT: Life extension multivitamin [2010-11]. The unique formulation VIMMORTAL for a multivitamin supplement was invented, refined, developed and licensed entirely from the Longecity community forums and made available for sale in [Forum Group]
	Folding @Home [2010-11] When Stanford launched the first ‘distributed computing’ project with a life science angle, LongeCity recognised the outreach potential of such initiatives and sponsored a friendly competition to bring more contributors on board and to accelerate the project. [Forum Group]
“Soil for SENS” [2005-6] Lead: J.Schloendorn. John turned to the LongeCity community and beyond in search for exotic soil samples that might contain microbes which could help to break down age-related protein build-up in humans. [ forum thread / publication]
	Mouse Studies @Home [2013] Lead: AgeVivo. Longecity supported the idea of setting up a network of “citizen scientists” looking to analyse the diet of their pet mice for life extension benefits.
‘Fight Aging’ for SENS [2013-15] Lead: Reason. While not its main platform, Longecity has always showcased the phenomenally successful ‘Fight Aging’ fundraiser in support of the SENS foundation co-ordinated by our former director Reason and other partners.
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	In addition to these community initiatives, Longecity has also ⇒ taken the crowdfunding approach to research projects.

review: LongeCity Crowdfunded Research Projects

Tue, 19 Jul 2016 02:05:23 +0000

Longecity’s approach to supporting scientific research has always been characterized by small-scale, high-impact projects sourced and steered by and in connection with its community. Years before ‘crowdfunding’ and ‘citizen science’ became well known concepts they were practiced at LongeCity.

Some examples of SCIENCE projects we have crowdsourced in the past:

	“Laser ablation of lipofuscin” [2009] Lead: N.Schooler (SENS/private). An attempt to use medical lasers to eliminate Alzheimer plaques, this was an early venture in Longecity crowdfunding. While results were not of satisfactory robustness, this project paved the way towards LongeCity taking a planned approach to quality control in community crowdfunding science. [More info]
“Mitochondrial uncoupling” [2010] Lead: Dr. J.Gruber (Singapore). Modulation of the incomplete coupling of electron transfer to ATP synthesis across the mitochondrial membrane has been proposed as a mechanism to slow aging. The project investigated this hypothesis in worms. [Follow-up interview]
	“Adult stem cells versus Alzheimer's” [2011] Lead: Dr. A.Stolzing (Germany). Aiming to use adult stem cells in the fight against age-related neurodegeneration such as Alzheimer's disease. Perhaps the most ambitious LongeCity funded project to date. [Publication]
“Modelling cryoprotectant toxicity” [2012] Lead: Dr. JP de Magalhães (UK). The innate toxicity of compounds used to protect against freezing damage limits their use for advancing the science of medical biostasis. Longecity crowdfunding helped generate new insights from gene expression profiling of endothelial cells exposed to ethylene glycol, thus helping to reveal molecular signatures helpful for future experiments on cryoprotectant toxicity [Publication]
	“Mitochondria gene therapy” [2013] Lead: Dr. M.O’Connor (SENS). Another perspective at the crucial role of mitochondria in aging, this project supported research into rejuvenating these ‘power plants’ of the cell. $21K was mobilized and lead directly to a much larger follow-up project
“Buckyballs & cancer” [2014] Lead: Dr. K.Moody (Ichor), the Longecity community got very intrigued about a research paper reporting to extend mouse lifespan with nanosize C60 ‘buckyballs’. Via crowdsourcing we promoted further independent investigation into C60 effects which, as a side effect also prompted some interesting vendor testing data.
-	-	-
	In addition to these specific research projects, LongeCity has ⇒ supported students via small grants, ⇒ established a research partnership and support strategy and ⇒ taken the same crowdsourcing approach to other community initiatives.

Assessing the effects of c60 on human cancer pr...

Mon, 08 Sep 2014 15:12:36 +0000

View attachment: c60re02.png

"Assessing the effects of c60 on human cancer proliferation in vivo"

is led by life-extension trailblazer Kelsey Moody. It is interesting that he turns the attention of his new venture Ichor Therapeutics to the potential health effects of 'buckyballs' - a topic that has received significant attention on LongeCity ever since it was claimed in a scientific report that rats fed on olive oil infused with these structures experience dramatically increased maximal lifespans. (Review here).
True to it mission, LongeCity hosts the leading international discussion forum on this topic. Previously, the LongeCity community has come together to fund further grassroots research on C60 in mice and these studies are on-going.

Meanwhile though, in keeping with the pioneer spirit often found on the LongeCity forums, reports have come in from people trialing C60 in olive oil on themselves. As Kelsey points out, the long-term safety of this has yet to be established, and this project is particularly interested in whether C60 in olive oil has any cancer-inducing properties. Conversely, it may be the case that the compound has a tumor–suppressing function.
To investigate this, the team plans to infuse a total of 25 mice with C60-olive oil of various strengths or with an inert ‘control’ solution, graft a human cancer cell line to the mice and study the results. (Full research proposal here)

If the fundraiser succeeds it will further support the revolutionary notion of stakeholder-oriented, grass-roots science which complements, challenges and enriches academic research at those junctures that the community actually cares about. Moreover and perhaps even more importantly the fundraiser will help to built capacity and community interface at a dedicated life-extension research facility. Already, Ichor has housed an intern on a LongeCity stipend (Report here- Members only). Ultimately, we hope to create a network of such community-friendly labs around the globe, to provide aspiring young scientists
with training and networking and all members with easily accessible sources of expert advice.

LongeCity has facilitated 'crowdfunding' well before many other platforms in use today. This year, we have decided to try to tap into the potential of these external sites, but to add something to the process: This project is the first one to run on an external fundraising page that has received an official ‘stamp of endorsement’ from LongeCity.
The team has mooted the project at LongeCity, submitted for formal peer review and informal members comments and the board looked into the ability of the team to use the donated money responsibly and to deliver success (Internal link here). In the end, the project received a high rating of 3 stars and LongeCity decided to match each dollar donation from our general funds. And, awesomely, a generous Member immediately stepped forward to match them as well!

This means we only need to raise $6.000 via the external crowdfunding page at indigogo. Please give generously and spread the word!

For any queries about the project to Kelsey and the team, please post below.

Honorary Member: Fred Chamberlain (boundlesslife)

Mon, 08 Apr 2013 22:02:47 +0000

View attachment: fred.jpg

In the early 1970's Fred Chamberlain, together with his wife Linda founded the cryonics corporations Manrise and the Alcor Society for Solid State Hypothermia, The latter continues until today as the Alcor Life Extension Foundation one of a very few cryonics providers.

Fred joined LongeCity in 2005 as boundlesslife and shared his thought and experiences with the community over the years.

He was placed in cryostasis at Alcor on 22 Mar 2012.

Suspension case report:
View attachment: casereportA1002FredChamberlain.pdf

His wife Linda remembers him in an 'Ode to Fred'
View attachment: OdeToFred.pdf

He was elected honorary lifetime member for 'services to cryonics'.

"Healthy Aging" is not enough

Sat, 09 Feb 2013 12:55:19 +0000

A Response to the "Compression of Morbidity" Mindset

"...there is no basis for the ardent hopes and positive statements made as to [its] safety and success[..], and [..] therefore, it would be a wrong, whether wilful or unknowing, to lead the people and perhaps governments at this time to believe the contrary;..."

I will come back to this quote shortly.

The popular and wide spread article about the need to support and fund the compression of morbidity called the "Longevity Dividend" is a good example of a solid piece detailing a need to fight aging. In it, the authors show the viability of slowing the aging process, urge people to support it, urge the government to direct funds to it, and urge places like the NIH to reserve more resources for it.

However, they don’t push for indefinite health-spans or indefinite life extension, here after referred to as indefinite life extension. They push rather for the 'compression of morbidity', or in other words, for more healthy years in the last period of a person’s average, traditional, 70- to 90- year life span.

“This compression of mortality and morbidity would create financial gains not only because aging populations will have more years to contribute, but also because there will be more years during which age-entitlement and healthcare programs are not used.”

S. Jay Olshansky, Daniel Perry, Richard A. Miller, Robert N. Butler, 2006

At the same time the authors work to discredit the pursuit of indefinite life extension. They suggest that altering genes would not be practical, useful, or ethical. They call indefinite life extension unrealistic and suggest that it is not feasible. Although they are not focused exclusively on compressing morbidity, as much of the gerontology community has been, they are still mired in old-school thinking.

The overall mindset includes older academic scholars who have grown through the younger, naïve dreaming stages (where people tend to think more about things like indefinite life extension) into the realm of more realistic endeavours like the compression of morbidity.

In response

We must never forget that we are cosmic revolutionaries, not stooges conscripted to advance a natural order of things that kills everybody.”

Alan Harrington

Achieving indefinite life extension is the most important, urgent, and time-sensitive cause ever undertaken in the history of humanity, and with all due respect, sentiments like those expressed by proponents of the compression of morbidity, though very noble and well meaning, are misleading and harmful to this cause.

Regardless of whether we ultimately find that we can achieve indefinite life extension or not, we need to go all the way and see. Our lives- this amazing shot at this incredible mysterious existence- depend on it. We can not afford to sell ourselves short on this.

If life is practical and useful, if choosing life over death is ethical, then whichever functional constructive approach to creating its indefinite healthy extension that we discover will be practical, useful, and ethical as well. Life is those things.

People are right when they say that it is not productive or healthy to over hype this cause, or anything for that matter. Incidental examples are not representative. Also we cannot afford to confuse this cause's efforts with hype when they are not. This is a real, urgent, life-or-death cause. Its components are by their very nature demanding, large, and extraordinary. They require reciprocating reflection, dialogue, and action.

This is more than a scientific endeavour; this cause demands work, development, and in depth sociological reform as well. The two need to work together and acknowledge each other, rather than occasionally (and some times more often) misunderstand each other. We work to help facilitate these and other aspects more fluently, as we continue growing toward where humanity needs this cause to go.

The number one reason why we need to choose indefinite life extension over the compression of morbidity is this:

We don’t have to know we can get there to go there,
but we do have to go there to get there.

Compression of Morbidity isn’t a bad thing per se. However, portraying to the public that indefinite life extension is not in the cards is.

If people think that they can not get indefinite life extension in time for them, they won’t fight nearly as hard as this cause needs them to.

People like Dr. Aubrey de Grey of the SENS Foundation, who work on strategies for ending aging, say that the first person to live to 1,000 might be 60 years old now. He’s not saying that the first person to live to 1,000 is alive now. There’s a big difference. “Might” means go and see; “is” means go and get. We aren’t going there to get indefinite life extension; we are going to see if it is there to get or not. Organisations like ImmInst, stress that the world can see indefinite life extension if it supports this goal with urgency.

When something is this important, allowing people to open their minds to the realities that breakthroughs may be around the corner is important.

To be sure though, we cannot announce that indefinite life extension is just around the corner, because we don’t know that. That’s not what this cause is saying. Those that suggest that we are saying things like that are wrong. Indefinite life extension may not be in the cards in any foreseeable future. If we never find it, and along the way we realize a compression of morbidity by say, 7 years, then great, that’s a great goal, and a much needed step. But these 7 years should not be the goal in and of itself.

It is not the goal in and of itself in the same way that getting the “No Coloreds Allowed” signs removed wasn’t the goal of the Civil Rights Movement or performing 50 more space launches to orbit the earth wasn’t the goal in getting to the moon. Martin Luther King Jr. stated the notion that it was no time for gradualism and that justice too long delayed was justice denied.

"We have also come to this hallowed spot to remind America of the fierce urgency of now. This is no time to engage in the luxury of cooling off or to take the tranquilizing drug of gradualism.”

“I have almost reached the regrettable conclusion that the Negro's great stumbling block in his stride toward freedom is not the White Citizen's Counciler or the Ku Klux Klanner, but the white moderate, who is more devoted to 'order' than to justice; who prefers a negative peace which is the absence of tension to a positive peace which is the presence of justice; who constantly says: 'I agree with you in the goal you seek, but I cannot agree with your methods of direct action'; who paternalistically believes he can set the timetable for another man's freedom; who lives by a mythical concept of time and who constantly advises the Negro to wait for a 'more convenient season.'

Shallow understanding from people of good will is more frustrating than absolute misunderstanding from people of ill will. Lukewarm acceptance is much more bewildering than outright rejection.”

Martin Luther King Jr.

They needed to set ambitious goals that went all the way.

“We choose to go to the moon. We choose to go to the moon in this decade and do the other things, not because they are easy, but because they are hard, because that goal will serve to organize and measure the best of our energies and skills, because that challenge is one that we are willing to accept, one we are unwilling to postpone, and one which we intend to win, and the others, too.”

“…even though I realize that this is in some measure an act of faith and vision, for we do not now know what benefits await us.

But if I were to say, my fellow citizens, that we shall send to the moon, 240,000 miles away from the control station in Houston, a giant rocket more than 300 feet tall, the length of this football field, made of new metal alloys, some of which have not yet been invented, capable of standing heat and stresses several times more than have ever been experienced, fitted together with a precision better than the finest watch, carrying all the equipment needed for propulsion, guidance, control, communications, food and survival, on an untried mission, to an unknown celestial body, and then return it safely to earth, re-entering the atmosphere at speeds of over 25,000 miles per hour, causing heat about half that of the temperature of the sun--almost as hot as it is here today--and do all this, and do it right, and do it first before this decade is out--then we must be bold.”

John F. Kennedy

They needed to go there. It is the same for this cause.

We don’t have to know we can get there to go there, but we do have to go there to get there. Things like the removal of “Coloreds Only” signs, orbits around the earth and 7-year dividends, are parts of it, but the struggle for cilvil liberties and the moon landing would not have reached their potential if the visionaries had not dreamt to go all the way, rather than hoped to go a portion of the way.

“The great French Marshall Lyautey once asked his gardener to plant a tree.
The gardener objected that the tree was slow growing and would not reach maturity for 100 years.
The Marshall replied, 'In that case, there is no time to lose; plant it this afternoon!’”

We have to plant the seed that we are undertaking the quest for indefinite life extension now. We have to take into consideration the fierce urgency of now; we have to have a dream; we have to shoot for the moon. We have to start now. We have to go there. We have to see if our lives are in the cards for us or not. Missing out on this chance to exist here because we don’t go there would be as big of a tragedy as if the Americas were still undiscovered, blacks were still segregated, and the moon were still untouched.

This is the next great human mission. Through blood, sweat and tears, progress, joys, and dreams, our ancestors have delivered us to this cusp at the end of the technology era, which is emerging into the grand new Transhuman era. In a way, we have been preparing through out all of human existence for this. We cannot let our ancestors down. This is an immense homage we owe to them for their great sacrifices and hard work, as well as an obligation that we owe to ourselves and all of our dear progeny of the future.

There is no time to waste. We must plant the seeds we have been handed, the seeds of the movement for indefinite life extension, now. We have to get going now.

Let me get back to that statement from the beginning -- and quote it in full this time:

"...there is no basis for the ardent hopes and positive statements made as to the safety and successful use of the dirigible balloon or flying machine, or both, for commercial transportation or as weapons of war, and that, therefore, it would be a wrong, whether wilful or unknowing, to lead the people and perhaps governments at this time to believe the contrary;..."

Rear Admiral George Melville (1901)

Those who 'know better' are often worn down by a lifetime of trying.
The pioneers of important concepts and causes made their discoveries and pioneered their areas when they were different ages. Albert Einstein was 26, Isaac Newton was 23, Werner Heisenberg was 24, Bill Gates was 20, Alexander the Great was 20, Neil Armstrong was 39, and Meriwether Lewis & William Clark were 32 and 36, respectively. Dr. Martin Luther King Jr. started advocating for the Civil rights of African Americans when he was 26, Christopher Columbus was 41, and Mahatma Gandhi was 45. In fact it is hard to think of any who were 50 or older. That is not though, to say that that there were not many great pioneers over the age of 50.

Those who kick against a prevailing mindset can expect ridicule,
even at the cusp of their breakthrough.

"...a physicist who professed such heresies is unworthy to teach science."

German Minister of Education,
when George Ohm's theory of electricity was published in 1827

We aren’t of those mindsets; we are of the mindset of one of the founders of the scientific method itself,

“But by far the greatest obstacle to the progress of science and to the undertaking of new tasks and provinces therein is found in this–that men despair and think things impossible.”

Francis Bacon

They say that necessity is the mother of invention. If people don’t want it, crave it, fight for it, and believe they can have it, they they are going to innovate at a much slower rate.

Fighters know this, and in their hearts, scientists know this as well.

“It is fatal to enter any war without the will to win it.”

General Douglas MacArthur

“100% of the shots you don’t take don’t go in.”

Wayne Gretzsky

We may not be able to get there, but we have to believe we can if we are to put forth the amount of effort that is needed to get it done in time for us if it is there.

“The universe is full of magical things, patiently waiting for our wits to grow sharper.”

Eden Phillpotts

We don’t intend to keep it waiting. The time is now.
For the love of life, we may not get there, but we have to go there, and we have to do it like our lives depend on it.

Eric Schulke

crowdsourced multivitamin

Wed, 19 Dec 2012 01:41:21 +0000

Extending maximum human lifespan will likely require a wide range of new biotechnology. Powerful interventions such as pharmaceuticals, stem cell technology, and gene therapy are in development but could be years or decades away from widespread implementation. During the intervening time the best way to ward off the ravages of disease and aging is to take care of yourself.

Members of LongeCity are keenly aware of this reality. That is why LongeCity forum discussions about exercise, nutrition, and supplements are very active and comprehensive. Members are constantly on the lookout for the latest research lending insight into which supplements are beneficial, cost-effective, and readily available.
Much has been made of the deficiencies of current multivitamin formulations and this has led to a community effort to design the “perfect multivitamin”.

In a long process of collaborative discussion, Members designed what in their view comes closer to the 'perfect' anti-aging supplement than any other product on the market.
LongeCity then found a partner in RevGenetics Ltd (FDA RegNo: 12757922694) to produce it.

Under the brand name VIMMORTAL the formula was promoted during 2011.Many members enjoyed the heavy discount that RevGenetics generously provided to LongeCity members.

After over a year of sales, members decided to revisit the formula. The inclusion of choline in particular proved controversial in light of current research. VIMMORTAL was stopped and a new group convened to collate suggested tweaks and improvements. The revised formula was relayed to the previous partner Revgenetics.

After many delays and extensions throughout 2012, it became clear eventually that Revgenetics was not going to take the second generation of the crowdsourced supplement further.
This is a setback for the project, in which LongeCity was at the forefront of connecting supplement sellers and consumers in an innovative dialogue at the cutting edge of nutritional supplement design. However, we are proud of this effort and the experience and data generated by it.

The VIMMORTAL formula is 'open source' and we are optimistic that another manufacturer/seller will see the opportunities of connecting directly with the life extension community to provide the 'ideal' supplement solution.

Check the Vimmortal project forum.

Carbon nanospheres almost double rat lifespan:...

Sun, 15 Jul 2012 01:29:58 +0000

by AgeVivo and Sven Bulterijs

more discussion of the paper in question in this thread in the C60 Health sub-forum
this article is a work in progress, it may change over time based on discussions and new information /

Introduction
In June of 2012 an article was published by French and Tunisian scientists showing that C60 dissolved in olive oil significantly extended lifespan in rats (Baati et al., 2012). The Kaplan-Meier survival curve showed almost a doubling of lifespan. C60 is the most well-known family member of the buckminsterfullerenes (so named by their Nobel-prize winning inventors after futurist Buckminster Fuller) made of carbon atoms.

Errors in the initial publication
After publication, in a great example of the effectiveness of public peer review, errors were piced up by members of the public. The authors decided to submit a correction (Baati et al., 2012b); The editor states: “The authors have provided explanations of how the errors were made during the preparation of graphics and images”.

One error was that two controls images (GAog and GAip) were the same image. This error does not affect the global conclusions. The authors explained that they put these figures in at the last moment and made a mistake.

However, the other reported error is impressive: It remains perplexing how the astonishing claim in the most important figure for biogerontologists (the Kaplan-Meier curve) in the paper escaped the notice of the authors, the editor and the peer reviewers: instead of 66 months reported as maximum lifespan for C60 treated rats in the original paper (Baati et al., 2012a), after the correction this is reduced to 54 months (Baati et al., 2012b)
The authors explained that this was caused by using a software program they were not familiar with, making survival lines diagonal instead of vertical. It could be argued that the correction was reflected in he original text. For example, the authors wrote that “the estimated median lifespan (EML) for the C60-treated rats was 42 months”: this is counted starting at age 10 months (beginning of experiment) which leads to 10+42=52 and is indeed aligned with the corrected graph but not the initially published version. Moreover it is straightforward to convert the uncorrected graph into the corrected graph, simply by decaying the x-axis at each diagonal line, to make it vertical.

However, the text describing the survival actually contained (and contains) partial descriptions of the uncorrected graph:
- the paper indicates the age “M38” at which there is 67% survival in the olive-oil-treated group - presumably, this would be “M33” or “M34” based on the corrected graph.
- the EML of the water-treated group was reported to be 22

To some, such confusions around the survival graph casts doubt over the scientific diligence of the author and the editor. Others have argued that the authors have a credible track record but lack experience in lifespan experiments

Strong life extensions reported
Even taking into account the correction, the authors still claim a dramatic effect on lifespan.

Water
The lifepan of the water-treated controls is standard compared to reported Wistar rat lifespans in the literature, if slightly long-lived already (Weindruch and Walford, 1988).

Olive oil
The mean lifespan of the olive oil and the water fed animals was quite similar but the maximal lifespan was increased by an astonishing 17 months. Many health interventions such as healthy diets and exercise have shown to extend the mean but not the maximal lifespan (Skalicky and Viidik, 1999) indicating that they promote health but do not change the rate of aging (de Magalhaes, 2006).

Olive oil has been repeatedly reported to have various health benefits (Bendinelli et al., 2011; López-Miranda et al., 2010; Owen et al., 2004; Perez-Jimenez et al., 2005). Although not all studies go in that direction. Some studies find some health benefits but no lifespan effect (Jacomelli et al. 2010).
Compared to other oils, one study reports the olive oil treatment reduced lifespan in stroke-prone spontaneously hypertensive rats (Ratnayake et al., 2000). Another study in Wistar rats found no difference in mean or maximal lifespan between olive oil and sunflower oil treated rats (Quiles et al., 2004).

What makes the lifespan claims for the olive oil treated rats stand out is that their maximal lifespan is larger than the values reported even for specific life extension studies. For example Weindruch and Walford (1988) report a table with caloric restriction experiments in rats (pg 50-52) where the lifespans for the ad lib. fed Wistar rats varies from 22 to 39 months of age and for the restricted ones from 19 to 46 months of age. Calorie restricted Wistar rats genetically engineered to express an antisense growth hormone construct had a maximum lifespan of 47 months and mean lifespan of 36 months (Shimokawa et al., 2003).

If one believes the figures and rules out a yet-unreported dramatic health effect of olive oil, one might speculate that at some stage during the experiment olive oil may have been contaminated by C60.

C60
The C60 survival is even more striking, with the few rats rats surviving past the age 50 months.

The survival graph indicates that the C60 rats all died between ages 51 and 54 months, which may surprise by its collective suddenness. The corresponding author stated in personal communication that the last two rats were euthanized while not being in very good shape, in accordance with local animal husbandry rules; therefore they may have lived longer, but this had not been documented in the paper. Still, having 4 of the 6 animals dying at such similar times (with a similar pattern for the olive-oil group) is somewhat surprising.

It was questioned whether the C60 group might have been accidentally restricted. It is well know that many compounds, especially when given mixed into the food, can reduce the appetite of the animals (Spindler, 2012). However, in this study the C60 was not mixed into the food and the body weight figures show no evidence of caloric restriction (on the contrary). It should however be noted weight is not always a good marker to estimate caloric intake (Spindler, 2012).

Statistics
It should be stressed that the number of rats in each group was only 6. It is disputed whether this number is or is not too small to draw any meaningful conclusion. Discussion on this point here .

Elements in support of the life extension result

As referenced in the article, there are some indications that fullerenes may have various health benefits, including:
- it has no acute or sub-acute toxicity in rodents (refs 5 to 15 in the paper). Of note, various reports of toxicity of fullerenes exist when dissolved in specific solvants (for a review, see Kolosnjaj, 2007)
- it can act as an antioxidant and is able to scavenge a large number of radicals per molecule (refs 3-6, 21, 44, 47-50 in the paper)
- it can act as a decomposition catalyst for O2.-/H2O2 (ref 4 in the paper)
- it can act as a cytochrome P450 inhibitor (in particular P450 2E1; ref 21 in the paper). In the paper, the authors note some prevention of depletion of reduced glutathione and induce from it that the free-radical scavenging effect is a better explanation.
- it can inactivate Kupffer cells (liver resident macrophages; ref 21 in the paper)
- it has hepatoprotective effects (ref 21 in the paper tests CCl4 toxicity)

Fullerene derivatives were reported to increase the culture density of a green algae (Pseudokirchneriella subcapitata) by 72%, to increase the lifespan of a crustacean (Ceriodaphnia dubia) by about 40%, and to have other positive effects on a plant and a fungus (Gao, 2011). Of course this evidence is at best circumstantial in support of a lifespan effect in mammals.
As a particular comparator study, a carboxyfullerene SOD mimetic extended the lifespan of non-short-lived mice by about 11% and rescued age-related cognitive impairment (Kevin, 2008), right. This much larger study is tentative evidence that buckminster fullerens may have some lifespan benefit.
Of note, Baati et al. (2012) has investigated C60 whereas the cited studies here above have used chemically modified versions of C60 that are expected to behave differently in vivo.

Conclusion
At LongeCity, we are particulary interested in maximum lifespan extension. This paper reported extraordinary findings in this regard and had to retract them to some degree. In a field rife with hype and 'snake oil', scientists, however reputable and objective, have to be extra careful about producing and reporting results. There are some indications that fullerenes may have various health benefits, so it may be premature to dismiss this paper. The study requires repetition in an independent laboratory. This case has illustrated the importance of open and transparent science for progress in life extension research.

References:
» Baati T et al (2012a). The prolongation of the lifespan of rats by repeated oral administration of [60] fullerene. Biomaterials 33(19): 4936-4946.
» Baati T et al (2012b). Corrigendum to “The prolongation of the lifespan of rats by repeated oral administration of [60] fullerene”. Biomaterials 33(26): 6292-6294.
» Bendinelli B et al (2011). Fruit, vegetables, and olive oil and risk of coronary heart disease in Italian women: the EPICOR Study. Am J Clin Nutr 93(2): 275-283.
» Gao J, Wang Y, Folta KM, Krishna V, Bai W, Indeglia P, Georgieva A, Nakamura H, Koopman B, Moudgil B. PLoS One. 2011;6(5):e19976
» Jacomelli M, Pitozzi V, Zaid M, Larrosa M, Tonini G, Martini A, Urbani S, Taticchi A, Servili M, Dolara P, Giovannelli L.
» Dietary extra-virgin olive oil rich in phenolic antioxidants and the aging process: long-term effects in the rat. J Nutr Biochem. 2010 Apr;21(4):290-6. Epub 2009 Apr 14.
» Kolosnjaj J, Szwarc H, Moussa F. Toxicity studies of fullerenes and derivatives. Adv Exp Med Biol. 2007;620:168-80.
» Lin F et al (2010). C20, the smallest fullerene. In: Sattler KD (ed.). Handbook of Nanophysics: Clusters and Fullerenes. CRC Press, Boca Raton.
» López-Miranda J et al (2010). Olive oil and health: summary of the II international conference onolive oil and health consensus report, Jaén and Córdoba (Spain) 2008. Nutr Metab Cardiovasc Dis 20(4): 284-294.
» de Magalhaes JP (2006). Species selection in comparative studies of aging and antiaging research. In: Conn PM (ed.). Handbook of Models for Human Aging. Elsevier Academic Press, Burlington, MA.
» Owen RW et al (2004). Olives and olive oil in cancer prevention. Eur J Cancer Prev 13(4): 319-326.
» Perez-Jimenez F et al (2005). International conference on the healthy effect of virgin olive oil. Eur J Clin Invest 35(7): 421-424.
» Kevin L. Quick, Sameh S. Ali, Robert Arch, Chengjie Xiong, David Wozniak, Laura L. Dugan. A carboxyfullerene SOD mimetic improves cognition and extends the lifespan of mice. Neurobiology of Aging 29 (2008) 117–128.
» Quiles JL et al (2004). Dietary fat type (virgin olive vs. sunflower oils) affects age-related changes in DNA double-strand-breaks, antioxidant capacity and blood lipids in rats. Exp Gerontol 39(8): 1189-1198.
» Ratnayake WMN et al (2000). Vegetable Oils High in Phytosterols Make Erythrocytes Less Deformable and Shorten the Life Span of Stroke-Prone Spontaneously Hypertensive Rats. J Nutr 130(5): 1166-1178.
» Shimokawa I et al (2003). Lifespan extension by reduction of the growth hormone-insulin-like growth factor-1 axis: relation to caloric restriction. FASEB J 17(9): 1108-1109.
» Skalicky M and Viidik A (1999). Comparison between continuous and intermittent physical exercise on aging rats: changes in patterns of spontaneous activity and connective tissue stability. Aging (Milano) 11(4): 227-234.
» Spindler SR (2012). Review of the literature and suggestions for the design of rodent survival studies for the identification of compounds that increase health and life span. Age (Dordr) 34(1): 111-120.
» Tang AC and Huang FQ (1995). Electronic structures of giant fullerenes with Ih symmtry. Physical Review B (Condensed Matter) 51(19): 13830-13832.
» van der Rijst MP et al (1955). Experiments to determine the nutritive value of the average diet consumed in the Netherlands, when fed to white rats ad libitum and under conditions of restricted consumption (70%). Voeding 16: 708.
» Weindruch R, and Walford RL (1988). The retardation of aging and disease by dietary restriction. Charles C. Thomas, Springfield.

more discussion of the paper in question in this thread in the C60 Health sub-forum

Cryonics

Tue, 21 Feb 2012 21:06:47 +0000

The following is a quick overview on Cryonics.

NB: The information below is periodically reviewed for accuracy, but LongeCity makes no representations or gives any warranties whatsoever that the following information is accurate and complete at any point in time. LongeCity accepts no responsibility or liability for information contained on this page. The discussion of cryonics service providers and services in no way entails any endorsement on part of LongeCity. The lead author of this page, its editors and other contributors from time to time may be affiliated with one of the service providers mentioned below. Without qualification to the foregoing disclaimers, LongeCity strives to present the following information in an objective and balanced manner. If you feel that information on this page is inaccurate or imbalanced please contact the LongeCity Support Email.

INDEX

Cryonics Overview
Existing Cryonics Organizations
Cryonics Services Offered
Sizes of the Organizations
Whole Body/Neuro Options
Cryopreservation and Yearly Fees
Human Cryopreservation Procedures
Funding Cryonics by Insurance

Cryonics Overview

Cryonics is based on the idea that future medicine will have capabilities well beyond those of current medicine, including the ability to cure all diseases, rejuvenate and repair damage incurred in the cryopreservation process — through the use of nanotechnology and other technologies. Cryonics can be an ambulance or time capsule to future medicine which can allow us to live many thousands of years or longer in youth and good health. Stored at very low temperatures there will be very little molecular motion in cryonics patients for tens of thousands of years, although most of us do not believe that we will have to wait anywhere near so long for future medicine.

Although cryonics patients must be legally dead before cryonics procedures to reduce or eliminate ischemic damage and ice formation can be applied, cryonicists do not believe that cryonics patients are dead in an ultimate sense. Nearly all the cells of the body are alive for quite some time after the heart stops — including neurons. A standby team can be used to minimize the time between pronouncement of death and cooling, cardiopulmonary support, etc. Cryonicists believe that the anatomical basis of mind can survive much longer than six minutes after stoppage of the heart in the absence of cooling — despite the inability of current medicine to revive patients without neurological damage after more than six minutes of cardiac arrest. (See Quantifying Ischemic Damage for Cryonics Rescue for more details.)

Existing Cryonics Organizations

For most of cryonics history (which began in the mid-1960s), all of the cryonics organizations offering cryonics services have been in the United States. In 2005 a cryonics organization was created in Russia (just northwest of Moscow) and there are plans for another cryonics organization in Australia to offer perfusion and storage of cryonics patients within a few years. LongeCity does not endorse any particular cryonics organization. The data below is taken from the cryonics organizations without LongeCity attempting to verify the accuracy of their claims or the extent of the services they claim to provide. If you are considering utilizing any of these organizations, you should conduct your own investigation.

NAME	LOCATION	INCORPORATED	NON-PROFIT ?
Alcor Life Extension Foundation	Scottsdale, Arizona	1972	Yes
American Cryonics Society (ACS)	Cupertino, California	1969	Yes
Cryonics Institute (CI)	Clinton Township, Michigan	1976	Yes
KrioRus	Moscow, Russia	2005	No
Oregon Cryonics	Salem, Oregon	2005*	No
Suspended Animation, Inc (SA)	Boynton Beach, Florida	2002	No
Trans Time, Inc.	San Leandro, California	1972	No
Yinfeng Cryomedicine	Jinan, Shandong, China	2016	No

Alcor Life Extension Foundation and the American Cryonics Society (ACS) are organized as 501©3 charitable organizations, whereas the Cryonics Institute (CI) is simply a non-profit corporation. Although Suspended Animation, Inc. (SA) is ostensibly a for-profit company, it is mainly engaged in research and development of cryonics capabilities financed by the principals of the Life Extension Foundation. By 2012 KrioRus had relocated to a facility closer to Moscow, but a newer facility is being built midway between Moscow and St. Petersburg.

Oregon Cryonics was incorporated in 2005, but accepted its first patient (a pet patient) in May, 2014. Jordan Sparks is the owner/operator, but he has plans for a Board of Directors or other mechanism to out-live him (to allow for the organization to continue).

Cryonics Services Offered

Not all cryonics services are offered by all cryonics organizations. Patient administration service is offered by cryonics organizations that sign-up Members who are to be cryopreserved upon legal death and maintain responsibility for those Members while they are Patient's in cryopreservation storage. Perfusion is the replacement of normal body fluid with cryoprotective solutions to reduce or prevent ice formation at cryogenic temperatures. Storage is the storage of a cryonics patient in liquid nitrogen. Standby/Stabilization/Transport (SST) involves standing by the bedside of a medically terminal patient destined to be cryopreserved, the application of a heart-lung resuscitator and ice-water cooling as soon as possible after declaration of death,and transport to a perfusion facility while tissues are still being stabilized at low temperature.

The following table represents the services which cryonics organizations say they provide.

*=simplification, see explanation
NAME	PATIENT ADMINISTRATION	PERFUSION	STORAGE	SST
Alcor	Yes	Yes	Yes	Yes
ACS	Yes	Yes*	No*	Yes*
CI	Yes	Yes	Yes	No*
KrioRus	Yes	Yes	Yes	No
Oregon Cryonics	Yes	Yes	Yes	No
SA	No*	No	No	Yes
Trans Time	Yes	No	Yes	No
Yinfeng Cryomedicine	Yes	Yes	Yes	Yes

All standby cases done for Alcor Foundation outside of Arizona, but inside the continental United States are handled by Suspended Animation, Inc (SA). Alcor does standby for Alcor Members who are terminal in Arizona, Hawaii, and Alaska as well as in Canada. SA does not provide SST services outside the continental United States for any organization.

The American Cryonics Society (ACS) states that it mainly contracts with Suspended Animation,Inc. (SA) for perfusion and standby/transport, and contracts with the Cryonics Institute (CI) for storage. ACS also states that it has equipment, contractors and volunteers which are available for use in perfusion and standby in California should the need arise, although this is far less sophisticated and formal than what SA provides. ACS creates and manages individual charitable trusts for its patients. ACS regards these trusts as an important feature of the benefit gained by being an ACS Member.

Cryonics Institute (CI) Members who reside in the continental United States have the option of contracting directly with SA if they desire professional SST.In some cases volunteers or paid funeral directors have provided these services to CI Members. SA will keep records of CI Members who have arranged to have SA SST, but does not continue any administrative responsibility after the patient has been cryopreserved.

Trans Time is currently storing patients, but (despite what their website says) is not currently seeking new Members or Patients.

Sizes of the Organizations

There are various ways by which organization size could be measured, but for the purposes of this section size is represented by the number of Members in the organization, the number of patients currently being stored in liquid nitrogen and the number of full-time paid staff in the organization. The figures below are for June 2019, and are based on the statements of the organization in question.

*=simplification, see explanation
NAME	MEMBERS	FUNDED MEMBERS	PATIENTS	STAFF
Alcor	1,697*	1,246*	170	9*
ACS	?*	?*	20*	1*
CI	1,802*	?*	175*	3*
KrioRus	N/A	N/A	68	05*
Oregon Cryonics	8*	N/A	7	4*
SA	N/A	N/A	N/A	3*
Trans Time	?	?	3	1?
Yinfeng Cryomedicine	51	51	6	11

The Membership statistics reported above are for living Members only. Both Alcor and CI patients are Members (except for the ACS patients at CI). The American Cryonics Society (ACS) has an organizational policy against publishing the number of Members it has in its organization. As ofJune 2019 the 20 ACS patients were all in storage at the Cryonics Institute (CI). ACS has had one part-time clerk to do office work and has otherwise relied on volunteers. The 175 patients in storage at CI includes the 20 ACS patients. KrioRus has no Membership program, and the method of counting patients is odd — a few are not stored by KrioRus. KrioRus has 3 full-time and 2 part-time employees as well as numerous volunteers.

CI has four paid staff (two full-time and two part-time), a few contractors and many volunteers. Accounting is done by CI Treasurer Pat Heller (a CPA) with auditing by another CI Director. Trans Time does not report its Membership numbers. Suspended Animation (SA) is a subcontractor which provides Standby/Stabilization/Transport (SST) only to other cryonics organizations (ACS, Alcor and CI), so it has no Members or Patients — so the reporting of Members or Patients for SA is "Not Applicable" (N/A). SA makes extensive use of subcontractors when needed.

As of June 2019, CI reported 172 pets, Alcor reported 88 pets, KrioRus reported 34 animals, and Oregon Cryonics reported 4 pets in cryopreservation. Oregon Cryonics is also preserving 5 humans and one pet chemically.

Alcor and CI member numbers are not directly comparable because the word "Member" has different meanings for the two organizations. Membership in CI provides the privilege of obtaining cryopreservation services: pet, DNA or human cryopreservation. Many join CI only to store DNA or pets or to support CI, including some Alcor Members. Some Alcor Members have even made arrangements to use CI as a "back-up". Alcor does not allow its Members to have Alcor as a "back-up". Prior to April, 2012, all Alcor Members had made arrangements (ie, funding and contracts in place) for human cryopreservation and SST, but in April 2012 the Associate Alcor Member program was introduced. Associate Alcor Members do not have any cryopreservation arrangements with Alcor. For June 2019 CI recorded 195 "Associate Members", although unfunded CI Members are comparable to Alcor Associate Members so these "Associates" have paid nothing and completed no form.

For June 2019, Alcor reported 1,527 living Members, 1,246 of whom had made arrangements for human cryopreservation, and 281 of whom were Associate Members. Of the 1,802 CI Members in June 2019, 252 of those had made arrangements for both human cryopreservation and standby/stabilization/transport (all with SA). In September 2015, CI ceased reporting how many of it Members have funding and contracts for cryopreservation. Historically, less than half of CI Members have been funded (prior CI statistics). Since 2006, CI offers a 'partnership' arrangement for CI Members for SA SST.

As noted in the previous section, Trans Time is currently storing patients, but (despite what their website says) is not currently seeking new Members or Patients.

Oregon Cryonics has an owner (Jordan Sparks) plus three full-time employees. OC has 9 Members, but is no longer accepting new Members..

Accounts of patient histories and membership growth can be found at:
--Cryonics Institute (CI) Patient Details
--Cryonics Institute (CI) Statistics Details
--Complete List of Alcor Cryopreservations
--Alcor Membership Statistics

Whole Body/Neuro Options

The term neuropreservation (or "neuro") generally refers to the practice of cryopreserving only the head rather than the whole body. A "neuro" is usually a whole head, not just the brain, but sometimes only the brain is cryopreserved. Keeping the whole head to preserve the brain is convenient for both perfusion and storage (the skull protects the brain). In some cases, however, "neuros" are brain-only. The following represent options various organizations say that they offer.

*=simplification, see explanation
NAME	WHOLE BODY	NEURO
Alcor	Yes	Yes
ACS	Yes	No*
CI	Yes	No
KrioRus	Yes	Yes
Oregon Cryonics	No	Yes
SA	N/A	N/A
Trans Time	Yes	Yes
Yinfeng Cryomedicine	Yes	No

Alcor states that its Members have the option of having their whole body cryopreserved or only their head ("neuro") — with different fees applicable to each choice. In June 2019, Alcor reported having 109 neuro, 61 whole body, and 4 neuro+whole body patients, whereas KrioRus reported 34 neuro and 34 whole-body patients. Trans Time has one whole body and two brains.

All CI Members with human cryopreservation arrangments are "whole body". ACS states that it does not have a policy against neuropreservation, but as long as it only uses CI as its subcontract or for storage it cannot offer neuro-cryopreservation as an option. Suspended Animation (SA) is a subcontractor which provides Standby/Stabilization/Transport only to other cryonics organizations, not storage, so the question of storage options with SA is "Not Applicable" (N/A).

Oregon Cryonics only stores heads and brains. As of June 2019 Oregon Cryonics was chemically preserving 5 human neuros and one pet neuro, and was cryopreserving 2 human neuros and 3 pet neuros.

Cryopreservation and Yearly Fees

Comparing fees for human cryopreservation and yearly Membership or Emergency Responsibility is difficult to summarize in table form because the policies, procedures and options between the cryonics organization are so different. A great deal of explanation is required. Note that the high prices for human cryopreservation are generally covered by life insurance policies. The following represent the fees that the following organizations state that they charge.

*=simplification,see explanation
NAME	WHOLE BODY	NEURO	YEARLY FEES
Alcor	$200,000*	$80,000*	$620*
ACS	$155,000*	N/A	$376*
CI	$28,000*	N/A	$120*
KrioRus	$36,000*	$12,000	None
Oregon Cryonics	N/A	$25,000*	None
SA	N/A	N/A	None
Trans Time	$150,000	$50,000	$96*
Yinfeng Cryomedicine	$290,000	N/A	N/A

To Alcor's yearly fee of $620 annual dues, those living in the United States and Canada must add $180 yearly SST fees for a total of $800 per year. A lifetime payment plan is also available. SST service is not available to Alcor Members outside of the US and Canada, but a $15,000 surcharge is added to whole body and neuro prices in the United Kingdom, and a $25,000 surcharge is added to the prices paid by those living in other countries. For details on Alcor pricing, see Schedule A: Required Costs and Suspension Funding Minimums.

The prices given for the American Cryonics Society (ACS) are intended to reflect comparable service to what Alcor provides. In fact, ACS has a very wide menu of options and prices available, including reference to a "California Procedure" which is intended to be distinguished from the"Michigan Procedure" offered by the Cryonics Institute. The yearly fee for an ACS Member is $376 for the first four years and $300 per year thereafter. For details on ACS options and fees, see:www.americancryonics.org.

The Cryonics Institute (CI) charges $28,000 for perfusion and storage of a Lifetime Member and $35,000 for a Yearly Member. These prices do not include funeral director costs or shipment to CI for non-local cases. (When CI was begun it was imagined that every state would have at least one cryonics service provider.) The Lifetime CI Member has paid a one-time $1,250 fee and the Yearly CI Member has paid a $75 initiation fee and is paying a $120 yearly fee. Discounts for additional family members and underage family members apply only to Lifetime Memberships. For service more comparable to what Alcor provides — including Standby/Stabilization/Transport (SST) — a Lifetime Member pays $88,000 and a Yearly Member pays $95,000. For details on CI pricing see Membership andDetails Concerning SA Standby and Transport for CI Members.

For $49,000 KrioRus states that it offers Russians (Europeans?) the option of shipment and storage at the Cryonics Institute in the USA.

Oregon Cryonics charges $25,000 to cryopreserve a whole head, $18,000 for a brain with braincase, and $14,000 for a brain without the braincase. Oregon Cryonics will chemically preserve a brain for as little as $1,000 (see Oregon Cryonics Service Fees for details).

As noted in previous sections, Trans Time is currently storing patients, but (despite what their website says) is not currently seeking new Members or Patients.

Suspended Animation (SA) is a subcontractor which provides SST only to other cryonics organizations, not Membership or storage, so the question of these options with SA is "Not Applicable" (N/A).

Human Cryopreservation Procedures

Human cryopreservation procedures are much too complex to be summarized effectively here.

Alcor's procedures are summarized on a page of the Alcor website called Alcor Procedures. But is it also very helpful to read actual case reports of Alcor patients in the Cryopreservation Case Reports section of the Alcor website library.

CI has a summary of its procedures on its website calledGuide to Cryonics Procedures. CI procedures do not include Standby/Stabilization/Transport (SST), though CI will advise Members on obtaining assistance through local funeral directors. CI Members residing in the continental United States who wish to obtain SST can do so by subcontracting with Suspended Animation, Inc. (SA).

Although the American Cryonics Society (ACS) has equipment and volunteers which could be used if necessary, ACS basically relies on SA for Standby/Transport and CI for Perfusion/Storage.The human cryopreservation procedures of Trans Time and KrioRus are not documented on their websites.

Funding Cryonics by Insurance
The cost of cryonics is many thousands of dollars, but most cryonicists cover these costs with life insurance policies that name a cryonics organization as beneficiary. Premiums of life insurance policies are most affordable for those who are young and healthy. It is not prudent to seek life insurance in old age or after a terminal illness (when life insurance may be unobtainable). Nor is it prudent to believe that cryonics arrangements can be made efficiently or successfully when in a terminal condition.

Rudi Hoffman sells the great majority of cryonics life insurance policies. It makes good sense to take advantage of Rudi's considerable expertise in matters of cryonics and life insurance. (A sincere and unpaid plug for Rudi.)

Metformin a life extension drug?

Fri, 09 Dec 2011 23:32:17 +0000

by Sven Bulterijs

For hundreds of years it has been known that a plant extract from the French lilac (Galega officinalis) improved the intense urination seen in diabetes patients. From this plant guanidine was extracted but it was too toxic for human use. In the 1920s another extract – galegine – of the French liliac was briefly used followed by synthetic analogs – Synthalin A and B. In the 1950s artificial drugs – phenformin, butformin and metformin – with a chemical similarity to guanidine became available for clinical use. In the 1970s however phenformin and buformin were withdrawn from the market because of the increased risk for lactic acidosis (1,2), a severe disease with a mortality rate of about 50% (3). A safer analog of these drugs, metformin, is now probably the most widely prescribed antidiabetic drug in the US (1). It is also used to treat polycystic ovary syndrome (PCOS), an endocrine disorder, leading to anovulation (failure to release the egg cell from the ovaries) (4).
Calorie restriction (CR) is the best investigated experimental technique to extend lifespan of a wide range of organisms from yeast to rats (5). Metformin has been suspected for quite a while to be a CR mimetic – a drug that mimics the effects of a CR diet. Indeed, Stephen Spindler found that short-term (8 weeks) of metformin supplementation mimicked 75% of the gene expression changes observed in long-term CR. In contrast, short-term (8 weeks) CR only mimicked 71% of gene expression changes (6). Thus the metabolic effects of metformin supplementation and CR are very similar and suggest that metformin will, like CR, extend the lifespan and reduce the incidence of many degenerative diseases.
Buformin, phenformin, and metformin have been shown to extend the mean and maximal lifespan in mice, rats, and C. elegans – a tiny round worm and one of the most popular model organisms in biological research (4,7,8). It also reduces spontaneous and carcinogen-induced tumor incidence in normal and cancer susceptible mice, rats and hamsters (9,10). Recently it was found that injection of metformin decreased tumor burden by a remarkable 72%, tumor volume by 50%, and multiplicity by 66% in a toxin-induced mice model for lung cancer (11). Epidemiological studies have shown that diabetes patients treated with metformin have a lower risk for cancer compared to those treated with other anti-diabetic drugs (12,13). The use of metformin as an adjuvant therapy in the treatment of cancer is currently under investigation. Finally, metformin also has a positive effect on a wide range of risk factors for coronary heart disease (CVD) such as decreases in plasma triglycerides, total cholesterol, LDL, Lp(a), free fatty acids, and CRP while slightly increasing HDL (4). However, a recent meta-analysis found no significant harm nor benefits of metformin therapy on cardiovascular events (14).

Fig. 1 Pathways influenced by metformin that explain its life extension properties. The blunt ending arrows indicate inhibition while the arrows indicate activation.

The mechanisms for lifespan extension by metformin are not completely understood yet but probably involve AMPK and its downstream target mTOR (fig. 1) (4). mTOR is also the target of the famous life extension drug rapamycin that increases lifespan in mice both when administered early and during middle life (15,16). mTOR inhibits autophagy thus metformin activates autophagy by inhibiting mTOR. Autophagy clears cells from dysfunctional organelles – such as mitochondria – and other junk that can impair normal cellular functions and thereby extends lifespan. mTOR stimulates protein synthesis and for still very incomplete understood reasons protein synthesis reduces lifespan. Therefore again metformin is expected to retard aging. If the cell cycle is arrested – that is the cell temporally stops dividing – and the cell continues to receive growth signals (mTOR stays active), it can lead to cell senescence – a state of permanent cell cycle arrest (4). Senescent cells secrete proinflammatory molecules, this has been termed the senescence-associated secretory phenotype, and can locally stimulate tumor growth (17). Metformin is expected to prevent cell senescence by removing the growth signal pressure. AMPK inhibits NAD(P)H oxidase, an enzyme whose action produces superoxide – a free radical. Metformin thus decreases free radical production (4). Free radicals are molecules that have an unpaired electron, they desperately try to find an extra electron to stabilize their configuration and in the process destroy other molecules by stealing their electrons. The free radical theory of aging is without doubt the most well known mechanistic aging theory. It was first proposed by Denham Harman in 1956 (18). Since then the failure of antioxidants to extend the lifespan has cast doubt on the validity of the free radical theory but still most biogerontologists think that free radicals do play a certain role. In fact some even suggest that the failure of antioxidants is expected because they undermine the bodies stress response (19). AMPK can be activated by: (i) binding of AMP, and (ii) phosphorylation by other enzymes. Metformin has clearly been shown to increase the phosphorylation of AMPK but the effects on AMP are disputed. Phenformin and buformin inhibits complex I of the respiratory chain, so maybe metformin does so too. Such an inhibition would decrease ATP – the universal energy currency for life – production and thereby increase AMP levels.

ADP + Pi ⇔ ATP
ADP + ADP ⇔ AMP + ATP

AMP acts as an activator for AMP and thus complex I inhibition would activate AMPK. This one year study found that metformin inhibits complex I (20) while another one found no such inhibition (21). This is good and bad news. The inhibition of complex I is responsible for lactic acidosis induced by phenformin and buformin and since metformin does not inhibit complex I it is much safer. Indeed, in a meta-analysis of published reports and controlled trials for a total of 36000 patient years of metformin exposure, Salpeter et al. found no cases of metformin-induced lactic acidosis (22). However, several case reports have been published in the literature (23). A common factor among all cases is that the patients have contra-indicators for the use of metformin such as renal problems and heart failure. Of the 47 patients with confirmed metformin-induced lactic acidosis by 1998 only 4 did not have any contra-indications for its use and all 4 recovered (24). The bad news is that complex I inhibition is expected to decrease free radical leakage (4). Metformin has been shown to prevent protein cross-linking (4).

Chemically metformin is very similar to aminoguanidine (fig. 2), one of the most researched inhibitors of glycation (for a review on glycation and protein cross-linking see 25). AGEs activate RAGE – a cell membrane receptor – leading to inflammation. Metformin has been shown to reduce inflammation in cells exposed to AGEs (26). Metformin reduces IGF-1 – a peptide hormone that stimulates growth. Mice with mutations in the growth hormone signaling pathway have lover IGF-1 levels and life 25-60% longer than control mice (27,28). Based on research in C. elegans and some suggestive evidence in mice (lower IGF-1 in the growth hormone pathway mutant mice) it has been concluded that decreasing IGF-1 will probably extend lifespan (29). Recently it was shown that metformin protects against replicative stress (30).

Fig. 2 Structural relationship between metformin and aminoguanidine. Both contain a guaninium-group (as is also found in the side chain of arginine).

In my recent review (4) I have suggested that AMPK might not be involved in life span extension by CR because of the inconsistent results of several studies on how CR influences AMPK (activation, no-activation, or inhibition). AMPK might however ’intersect’ with the ‘CR-pathway’ and thus I’ve termed metformin an ‘indirect CR mimetic’ (fig. 3). This model also explains why CR and metformin have some different metabolic effects.

Fig. 3 Metformin as an indirect CR mimetic. The blue dots represent different steps (protein cascade) in the ‘CR pathway’. Note that even though for simplicity the pathway is represented as a linear series of steps, in reality it will be a complex network that intersects with many other pathways. The double arrow between AMPK and ‘other signaling pathways’ illustrates that other signaling pathways can activate AMPK and thus influence the ‘CR pathway’ but that activation of AMPK, for example by metformin, can also activate other pathways that are independent of the ‘CR pathway’ (idem dito for the other double arrow) (see: ref. 4).

Rapamycin is a very expensive drug, about 500 USD a month for a daily dose of 2mg. Metformin, on the other hand, is extremely cheap and its side effects are more moderate. Metformin does inhibit vitamin B12 absorption in about 10% (but in some studies up to 30%) of treated patients (31,32). Thus blood levels vitamin B12 should be regularly tested. In conclusion we can say that metformin is an interesting candidate for a cheap and safe CR mimetic.

NOTE: Statements herein have not been evaluated by the FDA or any regulatory body. LongeCity does not promote the off-label use of any drug without appropriate medical supervision.

References:

(1) Hundal RS, Inzucchi SE. Metformin. New understandings, new uses. Drugs 2003;63:1879–1894.
(2) Bailey CJ, Day C. Metformin: its botanical background. Practical Diabetes Int 2004;21(3):115-117.
(3) Silvestre J, Carvalho S, Mendes V, Coelho L, Tapadinhas C, Ferreira P, Povoa P, Ceia F. Metformin-induced lactic acidosis: a case series. J Med Case Rep 2007;1:126.
(4) Bulterijs S. Metformin as a geroprotector. Rejuvenation Res 2011;14(5):469-482.
(5) http://www.longecity...tion-primer-r25
(6) Spindler SR. Use of microarray biomarkers to identify longevity therapeutics. Aging Cell 2006;5:39–50.
(7) Anisimov VN, Semenchenko AV, Yashin AI. Insulin and longevity: Antidiabetic biguanides as geroprotectors. Biogerontology 2003;4:297–307.
(8) Anisimov VN. Metformin for aging and cancer prevention. Aging 2010;11:1–15.
(9) Anisimov VN, Berstein LM, Egormin PA, Piskunova TS, Popovich IG, Zaberzhinski MA, Poroshina TE, Semenchenko AV, Provinciali M, Re F, Franceschi C. Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Exp Gerontol 2005;40:685–693.
(10) Anisimov VN, Egormin PA, Bershtein LM, Zabezhinskii MA, Piskunova TS, Popovich IG, Semenchenko AV. Metformin decelerates aging and development of mammary tumors in HER-2/neu transgenic mice. Bull Exp Biol Med 2005;139:721–723.
(11) Memmott RM, Mercado JR, Maier CR, Kawabata S, Fox SD, Dennis PA. Metformin prevents tobacco carcinogen-induced lung tumorigenesis. Cancer Prev Res 2010;3:1066-1076.
(12) Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JMM. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 2009;32(9):1620-1625.
(13) Currie CJ, Poole CD, Gale EAM. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 2009;52(9):1766-1777.
(14) Lamanna C, Monami M, Marchionni N, Mannucci E. Effect of metformin on cardiovascular events and mortality: a meta-analysis of randomized clinical trials. Diabetes Obes Metabol 2011;13(3):221-228.
(15) Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009;60:392–395.
(16) Miller RA, Harrison DE, Astle CM, Baur JA, Boyd AR, de Cabo R, Fernandez E, Flurkey K, Javors MA, Nelson JF, Orihuela CJ, Pletcher S, Scharp ZD, Sinclair D, Starnes JW, Wilkinson JE, Nadon NL, Strong R. Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci 2011;66:191–201.
(17) Coppé J-P, Desprez P-Y, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Ann Rev Pathol 2010;5:99-118.
(18) Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol 1956;11(3):298–300.
(19) Lane N. A unifying view of ageing and disease: the double-agent theory. J Theor Biol 2003;225:531-540.
(20) Stephenne X, Foretz M, Taleux N, van der Zon GC, Sokal E, Hue L, Viollet B, Guigas B. Metformin activates AMP-activated protein kinase in primary human hepatocytes by decreasing cellular energy status. Diabetologia 2011;54(12):3101-3110.
(21) Larsen S, Rabøl R, Hansen CN, Madsbad S, Helge JW, Dela F. Metformin-treated patients with type 2 diabetes have normal mitochondrial complex I respiration. Diabetologia 2011; [Epub ahead of print].
(22) Saleter S, Greyber E, Pasternak G, Salpeter E. Risk of fatal and non-fatal lactic acidosis with metformin in type 2 diabetes. Archives Int Med 2003;163:2294-2602.
(23) Roche C, Nau A, Peytel E, Moalic JL, Oliver M. Acidose lactique schevere par intoxication accidentele à la metformine: à propos de 3 observations. Ann Biol Clin (Paris) 2011;69(6):705-711.
(24) Misbin RI, Green L, Stadel BV, Gueriguian JL, Gubbi A, Fleming GA. Lactic acidosis in patients with diabetes treated with metformin. New Engl J Med 1998;338:265-266.
(25) http://www.longecity.../crosslinks-r20
(26) Ishibashi Y, Matsui T, Takeuchi M, Yamagishi SI. Beneficial effects of metformin and irbesartan on advanced glycation end products (AGEs)-RAGE-induced proximal tubular cell injury. Pharmacol Res 2011;[Epub ahead of print].
(27) Flurkey K, Papaconstantinou J, Harrison DE. The Snell dwarf mutationPit1^dw can increase life span in mice. Mech Ageing Dev 2002;123(2-3):121-130.
(28) Brown-Borg HM, Borg KE, Meliska CJ, Bartke A. Dwarf mice and the ageing process. Nature 1996;384:33.
(29) Barbieri M, Bonafè M, Franceschi C, Paolisso G. Insulin/IGF-1-signaling pathway: an evolutionary concerved mechanism of longevity from yeast to humans. Am J Physiol Endocrinol Metab 2003;285(5):E1064-1071.
(30) Halicka HD, Zhao H, Li J, Traganos F, Zhang S, Lee M, Darzynkiewicz Z. Genome protective effect of metformin as revealed by reduced level of constitutive DNA damage signaling. Aging (Albany NY) 2011;3(10):1028-1038.
(31) de Jager J, Kooy A, Lehert P, Wulffelé MG, van der Kolk J, Bets D, Verburg J, Donker AJM, Stehouwer CDA. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B12 deficiency: randomized placebo controlled trial. BMJ 2010;3401:c2181.
(32) Bauman WA, Shaw S, Jayatilleke E, Spungen AM, Herbert V. Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care 2000;23:1227-1231.

Calorie Restriction Primer

Fri, 18 Nov 2011 21:03:14 +0000

by Sven Bulterijs & Paul McGlothin,

Often described as the only proven intervention that extends mean and maximal life-span in mammalian species, it is also a lifestyle choice for the committed immortalist. But why and how does it work? How to begin and what are the downsides?

These and other questions are dressed in a short feature by Paul McGlothin, Co-author of “The CR Way” and
in a voiced slideshow by Sven Bulterijs, LongeCity Director and student in biochemistry and biotechnology.

-- Articleon Calorie Restriction by Paul McGlothin (.pdf)

-- Lectureon Calorie Restrictionby Sven Bulterijs (.pptx)