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Eternus Science

Neurohacker Collective put rigorous research into the formulation of their Qualia nootropic stack products which debuted in 2016. They now have turned their research to the riddle of aging and the decreased cellular energy that initiates many aging symptoms. The result is Eternus, a 36 ingredient formula designed to be the most comprehensive stack on the market for cell energy support, and delaying the effects of aging as long as possible.
Aging begins at the cellular level. The roughly 37 trillion cells in our bodies are performing trillions of metabolic functions each second. Decreases to the efficiency and energy of cellular function, underlies virtually all symptoms we associate with aging, from wrinkling skin and sagging muscles, to greater lethargy and brain fog, to poorer sleep and longer physical recovery times.
Comprehensive support for cell energy and efficiency lies at the bedrock of limiting the effects of the aging process, but it is an incredibly complex challenge. We all age, but the rate of aging and the negative symptoms associated with that process are highly variable. To make the rate and symptoms of aging as slow and subtle as possible, a nutritional formula must account for a broad range of cellular functions simultaneously.
These types of complex formulation requirements are where Neurohacker Collective separate themselves from most stack formulators. They specialize in formulation modeling premised on complex systems science, which incorporates dozens of ingredients dosed in precise synergistic relationships with each other, to support the body’s biochemical pathways to self regulate optimally. This approach is in contrast to a lot of pharma and nutra formulators who override those pathways to achieve an isolated benefit by externalizing side effects to other parts of the body, which can further exacerbate regulatory dysfunction.
The following is a deep dive into Eternus, which addresses cell energy and the aging process in at least 6 distinctive ways.

What is Eternus?

Eternus is a natural cell energy stack designed to comprehensively limit the negative effects of the aging process. It has been formulated by Neurohacker Collective, a San Diego-based company with a mission to create products that improve human performance by supporting our natural complex physiology rather than overriding it.

6 Ways Eternus Supports Cell Energy & Better Aging

1) Promotes a Fitter Mitochondrial Network

If your mitochondria don’t function properly, your cells will struggle to produce energy. With insufficient energy being produced, you’ll feel more tired and lethargic (R).
And poor mitochondrial health doesn’t only cause physical sluggishness.It also is linked to brain fog and neurodegenerative diseases, while improving mitochondrial function may reverse these conditions (R, R, R).
The mitochondria also initiate the production of steroid hormones, including cortisol and all sex hormones. That’s why malfunctioning mitochondria can cause hormone imbalances (R).
Another key function of the mitochondria is to commit cellular suicide – known as apoptosis – in response to excess stress, damage, or mutations. Evolutionarily, it is better for the damaged cells to commit suicide than to spread more oxidative stress, or to go on and damage other cells which can potentially develop into cancers (R).
Supporting the mitochondria and reducing oxidative stress generally protects the neurons by preventing apoptosis. In a small clinical study, a comprehensive natural approach (supplements, diet, lifestyle) sustainably reversed cognitive decline in 10 elderly patients. The program focused on reducing brain inflammation, and supporting the mitochondria and brain plasticity (R).
Eternus has a multitude of ingredients with research correlating to various aspects of improved mitochondrial health and function, including resveratrol (R), lipoic acid (R), n-acetyl-L-cysteine (R), and Coq10 (R).

2) Boosts Production of NAD+ & Optimizes NAD+: NADH Ratio

Nicotinamide adenine dinucleotide (NAD) is a coenzyme that consists of adenine and nicotinamide, and is found in all living cells.
NAD exists in two forms: NAD+ and NADH respectively. NADH contains 2 more electrons than NAD+.
Low NAD+ quickens aging. In mitochondria of young people, NADH can readily donate its electrons to generate NAD+. During the aging process, increased DNA damage reduces NAD+, leading to reduced SIRT1 activity and reduced mitochondrial function (R ).
In addition, during aging, the decline in the function of genes that control circadian rhythm can reduce NAD+ levels (R).
NAD+ also has compelling correlations to cognitive health. In a mouse model of Alzheimer’s disease, increasing NAD+ by supplementing with nicotinamide riboside restores cognitive function by increasing PGC-1alpha levels (R).
Supplementation with NAD+ intermediates, readily increases cellular and mitochondrial NAD+, and reverse many aging or disease processes associated with low NAD+ (R, R2). There is strong evidence that B vitamin levels have direct correlations to NAD+ production (R), with niacinamide (B3) in particular showing a particularly strong correlation (R). Eternus supplies a stack of B1, B2, B3, B5, B7, B9 and B12 vitamins in its formula.
While boosting NAD+ is a useful strategy, it’s also important to increase the NAD+ : NADH ratio. Increasing the cellular consumption of NADH is an additional lever toward that end. Calorie restriction induces an enzyme called Nrf2, which is considered to be a master regulator of cellular defense; it’s responsible for many cellular protection processes and involved in mitochondrial biogenesis (i.e., building new mitochondria). This enzyme then changes how other genes (and the enzymes the genes produce) express themselves, including a cellular detoxification enzyme called NQO1. In order to protect cells from potentially harmful agents, NQO1 uses NADH, resulting in lowering of cellular concentrations and an improved NAD+ : NADH ratio. Upregulating the Nrf2 → NQO1 pathway is the next piece of the puzzle. It’s part of addressing programmed aging.
A host of substances have evidence of boosting Nrf2 which are found in Eternus, such as R-Lipoic Acid (R), rosemary extract (R), french grapes extract (R?)

3) Elevates ATP Levels

Adenosine triphosphate, or ATP, is a cell’s “energy carrier” or “energy store” molecule. This is true of eukaryotic and prokaryotic cells, although the ATP production mechanism differs across the two types. ATP is the main source of energy for most cellular processes.
Low ATP levels are often found in people suffering from Chronic Fatigue Syndrome (R), and even moderate depletions of ATP have been linked to sizable increases in oxidative stress (R), while higher ATP levels have been correlated to increases in muscle mass (R) and increased capacity during high intensity activities (R).
Many ingredients in Eternus have been associated to increasing ATP levels including CoQ10 (R), and Eternus contains elevATP® specifically for that purpose, which contains a combination of trace minerals from ancient peat, including ionized magnesium and apple polyphenols, which has been correlated to increased ATP output in clinical studies (R).

4) Upregulation of Sirtuins

Sirtuins are a family of proteins critical to healthy aging. The regulate cellular health by performing critical biologic functions such as DNA expression.
When proteins are undergoing stress, acetyl groups are added to proteins as a response to changes induced by inflammation and oxidation.
Sirtuins remove these acetyl groups to keep the protein in service longer than usual, while simultaneously stabilizing the charge state of the carbon backbone in protein to resist any further changes in their shape. This allows your cellular proteins to live longer and you can save energy on other processes.
Sirtuins such as SIRT1 protects us from nitric oxide. When you have good SIRT1 levels and activity, nitric oxide will stimulate DNA repair genes (via deacetylation of FoxO1). Otherwise, nitric oxide will stimulate genes that will cause the cell to self-destruct (R).
Sirtuins play a major role in good sleep as well. SIRT1 regulates the strength (amplitude) and the duration of circadian gene expression in the retina by removing acetyl groups from key circadian clock regulators, such as BMAL1 and PER2.
In aged mice, SIRT1 levels in the SCN (circadian command center) are decreased, as are those of BMAL1 and PER2, causing a longer circadian period, a more disrupted activity pattern, and an inability to adapt to changes in the light entrainment schedule. Young mice lacking brain SIRT1 have similar effects to these aging-dependent circadian changes, whereas mice that overexpress SIRT1 in the brain are protected from the effects of aging (R).
Anything that increases NAD+, will increase SIRT1 activity. The relevant ingredients in Eternus which have already been listed to that end, but additionally, there is evidence that SIRT1 and SIRT3 activity increases from supplementation with lipoic acid,also found in Eternus, appearing to do so directly (R).

5) Activation of AMPK

AMPK(5′ AMP-activated protein kinase) is an enzyme that plays a key role in energy balance. All creatures from yeast to humans have this enzyme (R).
AMPK can detect the level of energy (number of ATP molecules) in a cell and helps regulate responses when it gets too low or high.
AMPK is produced in a number of tissues, including the liver, brain, fat cells and muscle (R).
AMPK in the hypothalamus senses our level of energy production in the body (energy in the form of ATP). It increases energy expenditure and can also increase appetite (when increased in the hypothalamus) (R).
When cellular energy is low, AMPK is activated and targets a range of processes, the net response of which is an increase in energy production and a coordinated decrease in energy (ATP) usage (R).
AMPK also inhibits the production of fatty acids, cholesterol, and triglycerides, and instead stimulates fat breakdown (R).
A multitude of ingredients in Eternus have been correlated to increasing the activation of AMPK, including Carnitine (R), gynostemma (R), CoQ10 (R), and resveratrol (R).

6) Support for Insulin Regulation

If you are insulin resistant, your brain will not get the message that insulin is trying hard to convey (that you have high levels of sugar in your bloodstream). In this way, insulin resistance promotes hunger. You eat and insulin is released, but your body tells you to eat some more despite the ability of insulin to act as a satiety hormone. Hence why obesity is linked to brain insulin resistance (R). 
When rats had their brain insulin receptors removed, they ate more, developed insulin resistance, and became obese (R). There is a correlation between insulin resistance and fat accumulation in the liver (R). Beyond a weight loss regimen and regular exercise, both of which can decrease insulin resistance, there are a number of supplement foods found in Eternus which can aid in this as well, such as magnesium (R),resveratrol (R),and lipoic acid (R).

What Makes Eternus A Unique Cell Energy and Aging Formula?

1) Comprehensive Targeting of Multiple Processes that Underlie Cell Energy & Aging

The white paper on Eternus lays out a very balanced, multi-pronged strategy in this formulation for addressing not only the 6 categories listed in this review, but also an accounting for the sub-categories and considerations comprising them. The scientists and medical professionals behind Eternus mapped out all the factors that affect cell health and aging to ensure their formulation addresses them all.

2) Synergistic Ingredients

Synergy is when a combination of ingredients produce an effect greater than the sum of its parts. Many ingredients in Eternus have more than a single positive effect and when you stack them together, some effects become stronger than when they are taken separately.

Eternus Ingredients

The Eternus formulation transparently lists all 38 ingredients comprising it and the dosing of each is consistent with the amounts the benefits that warrant their inclusion.

Positive Subjective Effects From Eternus

You can notice very significant improvements from Eternus within just a few days, such as:
- Noticeable increases in energy and vitality.
- Decreases in brain fog and more sustainable mental energy.
- Quicker recovery times from workouts and activities.
- Decreased pain and discomfort from decreased inflammation.
- Improved sleeping quality and easier transitions to wakefulness.

Bad Side Effects

Common negative side effects include:
- Possible upset stomach if Eternus is not taken with food.
- Potential restlessness if Eternus is taken late in the day.

Who is Eternus For?

Eternus is for anyone looking to maximize nutritional support for cell health and cell energy, particularly for those who are looking to delay the onset of age related decline as significantly and comprehensively as can be done through premium nutrition.The product comes with a 100-Day money back guarantee, and significant subjective improvements to vitality and energy are felt by most within the first week, providing quick evidence that cellular energy and efficiency is improving.

Buy Eternus

You can try Eternus by clicking here. Choosing the subscription option (which you can cancel anytime) gets you 50% off the first month supply, and using coupon code LONGECITY gets you an additional 15% off your first purchase.
A comprehensive cell energy product like Eternus can be a tremendous compliment to the foundations of good diet, exercise, and sleep, in holding back the hands of time for as long as possible, and sustaining a high physical and mental quality of life for decades to come.

The 18th-century Age of Enlightenment brought forth a paradigm shift in perceptions of the human condition and potential. The thinkers of the Enlightenment systematically articulated the case for rationality, science, and technology dramatically improving human well-being and overcoming what were previously considered to be immutable limitations. Those of us today who support the pursuit of indefinite life extension, rejuvenation biotechnology, and emerging research and its applications in a wide array of transformative fields are essentially continuing the project that the Enlightenment philosophers began. Although they had a much more rudimentary toolkit at their disposal, the most visionary minds among them were remarkably able to anticipate many aspects of our contemporary world and even to see beyond it. 
One such individual was Marie-Jean-Antoine-Nicolas de Caritat, Marquis de Condorcet (1743-1794), among the most talented polymaths, philosophers, economists, political scientists, mathematicians, administrators, and authors of the 19th century – a man who unfortunately lived far ahead of his time and whose life was claimed by the tumult of the French Revolution in 1794. Condorcet died in prison under mysterious circumstances, after running afoul of the murderous Jacobin faction that seized power in 1793-1794 and perpetrated a Reign of Terror that subverted the ideals of the Enlightenment. Shortly beforehand Condorcet completed a work that set forth the blueprint for human progress to come – the Esquisse d'un tableau historique des progrès de l'esprit humain (Outlines of a historical view of the progress of the human mind), published posthumously in 1795. At the end of this work, Condorcet briefly but insightfully articulated much of the terminology and conceptual framework that characterize many thoughts in the life-extension movement today. 

Condorcet divides human history into ten epochs, the first nine of which bring the human species to the era of the French Revolution; the tenth epoch is Condorcet’s vision for humankind’s future. Much of what Condorcet articulated has already come to pass – including dramatic improvements in agricultural and industrial processes, broadening of education, major progress toward gender equality, and decreases in the average number of children per family as economic development, education, and living standards have improved. Condorcet even posited an early version of what is today known as the “law of accelerating returns” (a phrase popularized in our era by Ray Kurzweil):

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 
--
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 
--
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

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). 


References

• Anisimov, V. (2003). Effects of Exogenous Melatonin—A Review. Toxicologic Pathology, 31(6), 589-603. http://dx.doi.org/10.1080/01926230390257885
• Ashok, B., & Ali, R. (1999). The aging paradox: free radical theory of aging. Experimental Gerontology, 34(3), 293-303. http://dx.doi.org/10.1016/s0531-5565(99)00005-4
• Aydogan, S., Yerer, M., & Goktas, A. (2006). Melatonin and nitric oxide. Journal Of Endocrinological Investigation, 29(3), 281-287. http://dx.doi.org/10.1007/bf03345555
• Bastide, N., Dartois, L., Dyevre, V., Dossus, L., Fagherazzi, G., Serafini, M., & Boutron-Ruault, M. (2016). Dietary antioxidant capacity and all-cause and cause-specific mortality in the E3N/EPIC cohort study. European Journal Of Nutrition, 56(3), 1233-1243. http://dx.doi.org/10.1007/s00394-016-1172-6
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View attachment: LCantiox.png

---- 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. 

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).

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.

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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

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

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

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.