Aging is an inseparable part of being alive. To live equals aging. There is no escaping the fact that the cells that make up our bodies are not designed to last forever. As they get older and have gone through more cycles of cell division, they function less and less well.
By Willem Koert
Scientists can say little with absolute certainty about the how and why of aging, but that doesn’t stop them from launching theories. In 2016, Portuguese chemists published an exhaustive review article on aging mechanisms, in which they listed 300 theories. We are now a few years further, and this number has undoubtedly only increased since then.
We are not going to confront you with all those theories in this blog. Many of them relate to factors beyond your control. In the first twenty years of the 21st century, for example, anti-aging researchers have devoted a lot of attention to longevity genes that should increase the chance of a long and healthy life. Scientists classify the contribution of our genes to aging as ‘intrinsic aging’.
Intrinsic versus extrinsic aging
Since we are mainly interested in things that we can change, let’s leave the theories about intrinsic aging for what they are. Instead, we focus on theories that might actually help you. These theories are about ‘extrinsic aging’. Extrinsic aging is aging that results from factors that you can influence, such as your lifestyle or the amount of stress you allow in your daily life.
Because scientific media still pays a lot of attention to the role of genes in longevity, it is easy to forget the role of lifestyle factors. Medical scientists estimate that about a quarter of the difference between individuals’ lifespans is due to genetic factors. As far as longevity is concerned, lifestyle and environmental factors may carry more weight than genes.
In a publication, which appeared in 2008 in PLoS Medicine, epidemiologists from the University of Cambridge calculated the effect of 4 simple lifestyle factors – not drinking a lot of alcohol, exercising daily, eating five pieces of fruit and vegetables a day and not smoking – on life expectancy. The scientists concluded that individuals who adhere to these 4 basic lifestyle rules live an average of 14 years longer than people who do not adhere to those rules.
A sub-optimal diet
A poor diet, which does not provide all the nutritional factors the body needs, can lead to cell damage. The body can replace those damaged cells, but this repair capacity is limited.
Cells can divide and form new cells to replace damaged and dead cells, but the more often they do this, the faster they age. In the long run, they lose their ability to function properly. The cells become less healthy, making biological processes less and less efficient.
American biochemist Bruce Ames, the inventor of the Ames test, suspects that we still do not know exactly how many nutrients, such as vitamins and minerals, we need to stay healthy. Based on his own fundamental research, Ames suspects that food scientists have estimated the intake of, for example, vitamin K and selenium at a level that does not cause direct or semi-acute cell damage.
However, Ames thinks that science has failed to look at processes that also require vitamin K and selenium, but whose health consequences only become visible in the longer term – read: at an advanced age. This implies that those who also want to stay healthy in the longer term may need vitamin K and selenium in larger amounts than the guidelines recommend. For this reason, Ames is a strong advocate of incorporating a basic multivitamin and mineral supplement into the daily diet.
Molecular research appears to confirm Ames’ theory. When researchers at the US National Institutes of Health measured the age of nearly 600 women at a cellular level, they found that using a simple multivitamin reduced their cell age by nearly ten years. This may mean that such a simple and cheap supplement can extend life by ten years.
According to some aging researchers, an aging body produces fewer hormones necessary for healthy functioning. This theory of endocrinological aging is the foundation of many hormonal anti-aging treatments offered by clinics. In those treatments, doctors try to compensate for the drop in hormone levels due to aging by administering hormones such as DHEA, testosterone and growth hormone.
Although users of hormonal anti-aging treatments typically experience a significant improvement in their quality of life, it is not clear whether these treatments on their own indeed extend life. In animal experiments, older lab rats with an elevated growth hormone level do not live longer, but rather shorter than normal. In addition, the hormones most frequently used in anti-aging treatments, such as testosterone and growth hormone, activate the mTOR molecule in cells. MTOR is a key molecule when it comes to processes such as building muscles, connective tissue and bones. Most anti-aging researchers see reducing mTOR activity as a key to a long and healthy life.
One of the most effective ways to reduce the activity of mTOR is to continuously consume several tens of percent fewer calories than your body actually needs. This gives the body a better chance of repair and detoxification processes and increases the lifespan of cells.
The life-prolonging effect of ‘caloric restriction’, as this approach is called, was discovered as early as the 1930s by researchers at Cornell University in experiments on lab rats. Already in these first studies, caloric restriction extended lifespan by 30-50 percent and at the same time reduced the risk of a variety of aging-related disorders.
Studies are currently underway in which researchers follow people on caloric restriction regimens for years. Although the first results are mainly positive, side effects have certainly come to light. For starters, a small group develops osteoporosis or anemia. A more frequent problem is that the caloric restriction reduces the quality of life. A permanent low intake of calories increases sensitivity to cold, irritability, lethargy, and feelings of irritation and reduced energy levels.
Although the research into caloric restriction is far from complete, the search for alternatives has already started, which consist of natural and pharmacological substances that mimic the effect of caloric restriction. A prominent one is resveratrol, a phyto-chemical naturally found in red grapes and, in small amounts, in berries,. In cells, resveratrol activates an enzyme called SIRT1. This enzyme also becomes active through caloric restriction. It allows cells to spend more energy on repair processes. We’ll be sharing a more about resveratrol and SIRT1 in follow-up blogs.
In a previous blog about the relationship between lifestyle and longevity, we wrote that a dietary pattern with a high intake of fruits and vegetables and exercise increases the chance of a long and healthy life. Those two factors seem to act on the same mechanism as caloric restriction.
This is probably because fruits and vegetables contain substances that do about the same as resveratrol, while exercise seems to work in a different way. Exercise may mimic the effect of caloric restriction by extracting significant amounts of energy from the body.
One aging theorem that has gained popularity in particular over the past decade is the cross-linkage theory. According to this theory, aging is due to the buildup of cross-linked protein complexes, which damage cells and inhibit important repair enzymes. This theory was launched in the 1940s by Johan Bjorksten. In the 1990s, the American biochemist Helen Vlassara called these complexes AGEs. AGEs is an abbreviation for ‘advanced glycation end products’. AGEs are more easily formed in the body when the glucose level is constantly high.
This explains why people are estimated to be older if their glucose level is continuously elevated. A lifestyle with a lot of exercise and a low intake of sugars and other fast-absorbing carbohydrates, which keep the glucose level low, can inhibit the formation of these complexes and thus slow down the rate of aging.
AGEs can also enter the body directly through foods. AGEs can be found in chips, cookies, fried snacks and other highly-processed industrial foods.
There isn’t much that everyone agrees on in contemporary nutritional science. But it is now beyond dispute that foods with a lot of ‘fast carbs’ and highly-processed foods are unhealthy.
At the turn of the century, free radical theory was the most popular theory of aging in applied health sciences. According to this theory, devised in the mid-1950s by the American chemist Denham Harman, aging occurs because aggressive molecules, the free radicals, continuously attack complex molecules in the body.
Harman initially suspected that these free radicals were formed by the action of various forms of radiation, but later he came to the conclusion that the cells themselves produced those free radicals. They were released when the mitochondria in the cells convert nutrients and energy, Denham theorized.
In the 1970s, 1980s and 1990s, longevity researchers hoped that high doses of antioxidants such as vitamin C, vitamin E and beta-carotene could slow down the cellular destruction of free radicals, but that turned out not to be the case. However, scientists still use the free radical theory when they want to demonstrate why a large amount of radioactive radiation or smoking is unhealthy. Exposure to radioactive radiation creates free radicals in the body, while cigarette smoke is full of free radicals.
According to Denham, mitochondria produce free radicals, which then damage the mitochondria over the long term. Thus, aging was not only a result of free-radical wrecking, but also a result of an increasingly serious cellular energy crisis due to less and less effective mitochondria. Towards the end of his academic career, Denham himself was pessimistic about the possibilities of solving this problem, but German biologists from the University of Jena took a different view.
The Germans did experiments in their laboratory with worms and mice, and discovered that there is a way to make organisms live longer via mitochondria. By challenging mitochondria, and by increasing the free radical production, cells were stimulated the cells to renew themselves. This resulted, among other things, in better functioning mitochondria.  This complex and paradoxical phenomenon is called hormesis.
Physical activity may be one way to achieve this type of hormesis. Ingestion of natural chemicals that challenge the energy production in mitochondria, like EGCG or alpha-ketoglutarate, may be another.
Yet another theory, which is remarkably popular in the academic community at the time of writing this blog, is the senescent cells hypothesis. According to this theory, we age because senescent cells that no longer function properly accumulate in our tissues. As a result, these tissues are less able to do what they are supposed to do. There are all kinds of systems out there that are supposed to clean up these stale cells, but the cells have found ways to get around them.
One way to limit the accumulation of aging cells is to prevent obesity. Another way is probably a diet high in vegetables and other sources of natural phenols. A phenol like fisetin, which is chemically closely related to quercetin, kills senescent cells in animal studies, thereby extending lifespan.
The theories we have mentioned in this blog are not mutually exclusive, but complement each other. We will return to these theories in future blogs, where we will discuss substantiated ways to extend the human life span and health span.
1 Da Costa JP, Vitorino R, Silva GM, Vogel C, Duarte AC, Rocha-Santos T. A synopsis on aging-Theories, mechanisms and future prospects. Ageing Res Rev. 2016 Aug;29:90-112.
2 Passarino G, De Rango F, Montesanto A. Human longevity: Genetics or Lifestyle? It takes two to tango. Immun Ageing. 2016 Apr 5;13:12.
3 Khaw KT, Wareham N, Bingham S, Welch A, Luben R, Day N. Combined impact of health behaviours and mortality in men and women: the EPIC-Norfolk prospective population study. PLoS Med. 2008 Jan 8;5(1):e12.
4 McCann JC, Ames BN. Vitamin K, an example of triage theory: is micronutrient inadequacy linked to diseases of aging? Am J Clin Nutr. 2009 Oct;90(4):889-907.
5 McCann JC, Ames BN. Adaptive dysfunction of selenoproteins from the perspective of the triage theory: why modest selenium deficiency may increase risk of diseases of aging. FASEB J. 2011 Jun;25(6):1793-814.
6 Xu Q, Parks CG, DeRoo LA, Cawthon RM, Sandler DP, Chen H. Multivitamin use and telomere length in women. Am J Clin Nutr. 2009 Jun;89(6):1857-63.
7 Bartke A. Can growth hormone (GH) accelerate aging? Evidence from GH-transgenic mice. Neuroendocrinology. 2003 Oct;78(4):210-6.
8 Papadopoli D, Boulay K, Kazak L, Pollak M, Mallette F, Topisirovic I, Hulea L. mTOR as a central regulator of lifespan and aging. F1000Res. 2019 Jul 2;8:F1000 Faculty Rev-998.
9 McCay CM, Crowell MF, Maynard LA. The effect of retarded growth upon the length of life span and upon the ultimate body size. 1935. Nutrition. 1989 May-Jun;5(3):155-71.
10 Fontana L, Partridge L, Longo VD. Extending healthy life span–from yeast to humans. Science. 2010 Apr 16;328(5976):321-6.
11 Ravussin E, Redman LM, Rochon J, Das SK, Fontana L, Kraus WE, Romashkan S, Williamson DA, Meydani SN, Villareal DT, Smith SR, Stein RI, Scott TM, Stewart TM, Saltzman E, Klein S, Bhapkar M, Martin CK, Gilhooly CH, Holloszy JO, Hadley EC, Roberts SB; CALERIE Study Group. A 2-Year Randomized Controlled Trial of Human Caloric Restriction: Feasibility and Effects on Predictors of Health Span and Longevity. J Gerontol A Biol Sci Med Sci. 2015 Sep;70(9):1097-104.
12 Dirks AJ, Leeuwenburgh C. Caloric restriction in humans: potential pitfalls and health concerns. Mech Ageing Dev. 2006 Jan;127(1):1-7.
13 Chung JH, Manganiello V, Dyck JR. Resveratrol as a calorie restriction mimetic: therapeutic implications. Trends Cell Biol. 2012 Oct;22(10):546-54.
14 Iside C, Scafuro M, Nebbioso A, Altucci L. SIRT1 Activation by Natural Phytochemicals: An Overview. Front Pharmacol. 2020 Aug 7;11:1225.
15 Hofer T, Fontana L, Anton SD, Weiss EP, Villareal D, Malayappan B, Leeuwenburgh C. Long-term effects of caloric restriction or exercise on DNA and RNA oxidation levels in white blood cells and urine in humans. Rejuvenation Res. 2008 Aug;11(4):793-9.
16 Bjorksten J. Pathways to the decisive extension of the human specific lifespan. J Am Geriatr Soc. 1977 Sep;25(9):396-9.
17 Noordam R, Gunn DA, Tomlin CC, Maier AB, Mooijaart SP, Slagboom PE, Westendorp RG, de Craen AJ, van Heemst D; Leiden Longevity Study Group. High serum glucose levels are associated with a higher perceived age. Age (Dordr). 2013 Feb;35(1):189-95.
18 Uribarri J, Cai W, Peppa M, Goodman S, Ferrucci L, Striker G, Vlassara H. Circulating glycotoxins and dietary advanced glycation endproducts: two links to inflammatory response, oxidative stress, and aging. J Gerontol A Biol Sci Med Sci. 2007 Apr;62(4):427-33.
19 Schwingshackl L, Schwedhelm C, Hoffmann G, Lampousi AM, Knüppel S, Iqbal K, Bechthold A, Schlesinger S, Boeing H. Food groups and risk of all-cause mortality: a systematic review and meta-analysis of prospective studies. Am J Clin Nutr. 2017 Jun;105(6):1462-73.
20 Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol. 1956 Jul;11(3):298-300.
21 Harman D. The biologic clock: the mitochondria? J Am Geriatr Soc. 1972 Apr;20(4):145-7.
22 Ristow M, Schmeisser S. Extending life span by increasing oxidative stress. Free Radic Biol Med. 2011 Jul 15;51(2):327-36.
23 Merry TL, Ristow M. Mitohormesis in exercise training. Free Radic Biol Med. 2016 Sep;98:123-130.
24 Tian J, Geiss C, Zarse K, Madreiter-Sokolowski CT, Ristow M. Green tea catechins EGCG and ECG enhance the fitness and lifespan of Caenorhabditis elegans by complex I inhibition. Aging (Albany NY). 2021 Oct 4;13(19):22629-48.
25 Bayliak MM, Lushchak VI. Pleiotropic effects of alpha-ketoglutarate as a potential anti-ageing agent. Ageing Res Rev. 2021 Mar;66:101237.
26 McHugh D, Gil J. Senescence and aging: Causes, consequences, and therapeutic avenues. J Cell Biol. 2018 Jan 2;217(1):65-77.
27 Maduro AT, Luís C, Soares R. Ageing, cellular senescence and the impact of diet: an overview. Porto Biomed J. 2021 Feb 11;6(1):e120.
28 Meccariello R, D’Angelo S. Impact of Polyphenolic-Food on Longevity: An Elixir of Life. An Overview. Antioxidants (Basel). 2021 Mar 24;10(4):507.
29 Yousefzadeh MJ, Zhu Y, McGowan SJ, Angelini L, Fuhrmann-Stroissnigg H, Xu M, Ling YY, Melos KI, Pirtskhalava T, Inman CL, McGuckian C, Wade EA, Kato JI, Grassi D, Wentworth M, Burd CE, Arriaga EA, Ladiges WL, Tchkonia T, Kirkland JL, Robbins PD, Niedernhofer LJ. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018 Oct;36:18-28.