Nutritional compounds, such as resveratrol can oppose aging …

How Effective Are Aging Theories?
Of increasing interest is the study of specific compounds suggested by specific molecular aging theories to lengthen lifespans and improve age-related biomarkers in mice specifically bred for these purposes
By Will Block

The secret of genius is to carry the spirit of the child into
old age, which means never losing your enthusiasm.

— Aldous Huxley

B iological aging is a physiologic state in which there is a progressive decline of organ functions, accompanied by the development of age-related diseases that lead to premature death. Unfortunately, at the end of the first decade of the 21st century, a comprehensive knowledge of the aging process is still in the future. Even so, aging researchers agree that there is substantial variability in aging rates among different species and that genes are important. Findings, especially in the gene arena, are paving the way to greater understanding, and this in turn will lead to applications that determine their effectiveness.

Scientists have been able to show, through the use of model organisms, that alterations in specific genes can extend lifespan. This has been found to be true in a number of different species, including yeast, nematodes, fruit flies, and in mice, although less so as the complexity of the organisms increases. Gene manipulation is not currently feasible in most humans, although it soon may be.

In spite of the value of gene changes, even in relatively simple organisms, the mechanisms of aging remain to be clarified. In the higher model organisms such as in mice (with a lifespan of about three years), there have been few experiments that have directly tested the variety of mechanisms hypothesized to explain biological aging. Consequently, much of the evidence to date is correlative.

Specific Compounds to Counter Aging

Of great interest is the study of specific compounds suggested by specific molecular aging theories to lengthen lifespans and improve age-related biomarkers in mice specifically bred for these purposes. What works in mice is likely to work in humans. Nevertheless, age-related testing of mammals has frequently not been reproducible. This is due to the relatively small numbers of animals used in most studies, along with the difficulty of maintaining strict protocols. However, progress is now speeding up, due to a number of technological advances, including the running of parallel experiments at several internationally recognized centers. Before something can be tested, however, it is useful to have a theory of aging, of which many have been hypothesized. The most promising biological theories, with descriptions of the underlying mechanisms and findings to date, follow:

Free-Radical Theory

This is a big idea, and one of the most momentous. It holds that free radicals (unstable and highly reactive organic molecules, also called reactive oxygen species) create oxidative stress damage that gives rise to symptoms we recognize as aging. Denham Harmon, MD, PhD, formally proposed this theory in a 1956 paper.1 Since then, many thousands of papers have been published on this subject, including a summing up by Dr. Harman in 2009: “Origin and Evolution of the Free Radical Theory of Aging: a brief personal history, 1954–2009.”2

In “Origin and Evolution …,” Dr. Harman—who takes supplements and is now 94 years of age—states that:

[T]he basic chemical process underlying aging was first advanced as the free radical theory of aging (FRTA) [by himself] in 1954: the reaction of active free radicals, normally produced in the organisms, with cellular constituents initiates the changes associated with aging. The involvement of free radicals in aging is related to their key role in the origin and evolution of life.

The rate of oxygen radical generation
in tissues, rather than the antioxidant
capacity, is what limits lifespan.

As early as 1957, it was demonstrated that the mean lifespan of mice could be increased by antioxidants.3 Indeed, in one of the earliest studies, a 20 per cent increase in the half-survival time of a particular strain of mice was achieved by adding either the amino acid cysteine, 2-mercaptoethylamine, or 2,2’-diaminodiethyl disulfide to their diet. The half-survival time of the controls was about 8 months, whereas that of the animals treated as above was about 10 months.

Maximum Lifespan Potential

Regardless of this, in the many years that have passed, while antioxidants have been shown to have many healthful properties and may reduce the risk of cancer and atherosclerosis, most studies with antioxidants have not found antioxidants to determine maximum lifespan. A review published in 2002 proposed that this evidence strongly suggests that the rate of oxygen radical generation in tissues, rather than the antioxidant capacity, is what limits lifespan.4 In 16 studies on lifelong experimental modifications of antioxidant levels by supplements, drugs, or transgenic techniques, only four found some increase in maximum lifespan potential (MLSP), whereas in the other 12, MLSP did not change. Consequently, they suggested that while antioxidants can help to avoid premature death and increase mean lifespan, they are not likely to be effective in extending maximum lifespan.

The Rate of Free Radical Generation as Cause

However, the rate of the generation of free radicals by mitochondria has been identified by many researchers (including Dr. Denham Harman) as a probable major cause of aging. And in caloric restriction studies in rodents, researchers have found significant decreases of free radical generation by mitochondria without a consistent effect on antioxidant capacity. It is strongly suggested that a far better strategy for MLSP enhancement is to take supplements that are capable of reducing the generation of free radicals by mitochondria, rather than simply taking antioxidants that disarm excess free radicals.

Quercetin has been shown to reduce free radical havoc in mitochondria by uncoupling mitochondrial respiration,5 as has conjugated linoleic acid (CLA).6 It is interesting to note that olive oil as a food induced the highest uncoupling mechanisms in rat brown adipose tissue, as compared to sunflower oil, palm oil, and beef fat. This may be a significant factor in the health benefits of the “Mediterranean Diet.”

According to Durk Pearson & Sandy Shaw, “The bottom line is that this new perspective does not undermine the free radical theory of aging; in fact, it supports it. Taking the right amounts of the right antioxidants is still a good idea, but in the long run, it appears it will be necessary to reduce the free radicals created by mitochondria to increase maximum lifespan.” (See “Why Antioxidants Do Not Necessarily Prevent Aging Due to Free Radicals” in Life Extension News, Volume 5 No. 6, December 2002.)

A far better strategy for MLP
enhancement is to take supplements
that are capable of reducing the
generation of free radicals by
mitochondria, rather than
simply taking antioxidants that
disarm excess free radicals.

Dr. Harman reports in his “brief personal history,” that the FRTA came exceedingly close to Nobel Award recognition, but failed to achieve this stature because Peter Medawar (himself a Nobel Prize winner for Medicine in 1960), who was about to endorse Dr. Harman and his theory, took ill and died. In 1995, there was a large write-in effort to the Nobel Prize Committee on Harman’s behalf for the Nobel Prize; this was unsuccessful. Also in 1995, there was yet another attempt to have Harman nominated for the Nobel Prize. Subsequent attempts were organized, but measures taken in 1996 and 1997 were also unsuccessful. Too bad! Nobel Prize acknowledgment could have sped the development of new knowledge about aging.

Mitochondrial Theory

This may be thought of as a special case of the FRTA. In fact, in 1972, Dr. Denham Harman proposed what is now called the mitochondrial theory of aging (MTA), as an extension and refinement of his earlier (1956) free radical theory of aging. The theory, which involves the role of mitochondrial function and dysfunction in aging and longevity, is supported by much circumstantial evidence. The MTA is based on the damage caused by oxidative stress within mitochondria. This leads to a vicious cycle in which damaged mitochondria produce increased amounts of reactive oxygen species (ROS), leading in turn to progressive increases in damage. Importantly, if aging results from oxidative stress, it may be corrected by environmental, nutritional, and pharmacological strategies.

A number of studies have found an inverse correlation between the rate of respiratory ROS production and lifespan. In fact, a vast body of data has accumulated linking mitochondrial redox metabolism to the aging process. First, current evidence indicates that maintenance of dietary sufficiency of folate throughout the lifespan is important for preserving mitochondrial DNA. Similarly, a growing number of dietary interventions have been demonstrated to modulate mitochondrial ROS production, detoxification, and oxidative damage repair.

Many (but not all) of these dietary interventions are associated with lifespan extension, or protection against age-related disease, in mammals. Emerging nutraceuticals such as resveratrol are showing promise as modulators of mitochondrial redox metabolism capable of eliciting beneficial outcomes that are similar to those of caloric restriction.

If the goal of dietary interventions impacting mitochondrial redox metabolism is to promote the health of aging populations, rather than to extend lifespan per se, then these approaches hold significant promise.

Other nutrients involved in mitochondrial metabolism that may provide clinical benefit include the essential minerals and the B vitamin group; vitamins E and K; the antioxidant and energetic cofactors alpha-lipoic acid, and coenzyme Q10 (CoQ10).7 Also, the trophic nutrients acetyl L-carnitine, glycerophosphocholine (GPC), and phosphatidylserine (PS) provide mitochondrial support and conserve growth factor receptors. The omega-3 fatty acid docosahexaenoic acid (DHA) is enzymatically combined with GPC and PS to form membrane phospholipids for nerve cell expansion. Practical recommendations are presented for integrating these safe and well-tolerated orthomolecular nutrients into a comprehensive dietary supplementation program for brain vitality and productive lifespan. Cumulative damage from ROS over decades may well be the final determinant of maximum lifespan.

DNA Damage Theory

Another special case of the FRTA, where oxidative stress damages DNA. The causes of such damage include chemical reactions that mutate DNA and/or interfere with DNA replication. Although both mitochondrial and nuclear DNA damage can contribute to aging, nuclear DNA is the main subject of this analysis, the damage of which can contribute to aging either indirectly (by increasing apoptosis or cellular senescence) or directly (by increasing cell dysfunction).

Mitochondrial Hormesis (Mitohormesis) Theory

For nearly 80 years, it has been known that the restriction of calories, while maintaining adequate amounts of nutrients, can extend maximum lifespan in lab animals. This effect may be due to increased formation of free radicals within the mitochondria causing a secondary induction of increased antioxidant defense capacity. Of course, as anyone who has been scientifically awake in the 21st century knows, resveratrol has been found to mimic many of the advantages of caloric restriction.8

Telomere Theory

Telomeres (structures at the ends of chromosomes) have experimentally been shown to shorten with each successive cell division. Shortened telomeres activate a mechanism that prevents further cell multiplication. This may be an important mechanism of aging in tissues like bone marrow and the arterial lining where active cell division is necessary. Importantly, mice lacking telomerase enzyme do not show a dramatically reduced lifespan, as the simplest version of this theory would predict. N-acetylcarnosine in an eye drop lubricant has been recently found to help prevent telomere shortening.9

Reproductive-Cell Cycle Theory

This theory holds that aging is regulated by reproductive hormones that act in an antagonistic pleiotropic manner (when a single gene influences multiple phenotypic traits) via cell-cycle signaling. This in turn promotes growth and development early in life in order to achieve reproduction. But later in life, in a futile attempt to maintain reproduction, functions become dysregulated and the pace of senescence is increased.

Error Accumulation Theory

This theory involves the idea that aging results from chance events that escape the “proof reading mechanisms,” and consequently gradually damage the genetic code.

Somatic Mutation Theory

The somatic mutation theory is the biological theory that aging results from damage to the genetic integrity of the body’s cells.

The Viral Theory of Aging

This theory holds that viral infection appears to be the most likely cause of the other 70% of DNA damage in cells not exposed to smoking and sun light. This other DNA damage causes the cells to stop dividing or induces apoptosis (cell suicide), damages thought to be the common pathway causing both cancer and aging.

Evolutionary Theories

Enquiries into aging evolution explain why almost all living things weaken and die with age. The exceptions, such as rockfish and naked mole-rats, are highly informative.

Wear-and-Tear Theory

This entails the general idea that changes associated with aging are the result of chance damage that accumulates over time.

Autoimmune Theory

The autoimmune theory holds that aging results from an acceleration in autoantibodies that attack the body’s tissues. Diseases such as atrophic gastritis and Hashimoto’s thyroiditis (associated with aging) are probably autoimmune in this way.

For the future to unfold in a way that
delivers the goods of more and
better health, the process of
theory triage must continue.

Accumulative-Waste Theory

This theory contends that a buildup of cells of waste products presumably interferes with metabolism.

Aging-Clock Theory

The aging-clock theory avers that aging results from a preprogrammed sequence, as in a clock, built into the operation of the nervous or endocrine system of the body. In rapidly dividing cells the shortening of the telomeres would provide just such a clock. This idea is in direct contradiction with the evolutionary based theory of aging.

Cross-Linkage Theory

The cross-linkage theory holds that aging results from accumulation of cross-linked compounds that interfere with normal cell function. First proposed in 1942 by Dr. Johan Bjorksten [see the mini-bio for advisor Dr. Don Kleinsek], this theory encompasses aging diseases such as sclerosis, a declining immune system and the most obvious example of cross-linking, loss of elasticity in the skin.

Reliability Theory of Aging and Longevity

This general theory encompasses systems failure, enabling researchers to predict the age-related failure kinetics for a system of given architecture and given reliability of its components. Reliability theory predicts that even those systems that are entirely composed of non-aging elements (with a constant failure rate) will nevertheless deteriorate (fail more often) with age, if these systems are redundant in irreplaceable elements. Aging, therefore, is a direct consequence of systems redundancy.

The Dustbin of Theories

This by no means exhausts all of the biological theories postulated to explain the aging process. And there are undoubtedly many new theories that will arise, as others fall prey to experimental evidence or its lack. One thing is clear … for the future to unfold in a way that delivers the goods of more and better health, the process of theory triage must continue. Biomedical science is driven onward by precisely the sense that there are truths out there to be discovered, truths that once discovered will form a permanent part of human knowledge, and make us all healthier.


  1. Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol 1956 Jul;11(3):298-300.
  2. Harman D. Origin and evolution of the free radical theory of aging: a brief personal history, 1954-2009. Biogerontology 2009 May 24 [Epub ahead of print].
  3. Harman D. Prolongation of the normal life span by radiation protection chemicals. J Gerontol 1957 Jul;12(3):257-63.
  4. Barja G. Rate of generation of oxidative stress-related damage and animal longevity. Free Radic Biol Med 2002 Nov 1;33(9):1167-72. 5.
  5. Dorta DJ, Pigoso AA, Mingatto FE, Rodrigues T, Pestana CR, Uyemura SA, Santos AC, Curti C.Antioxidant activity of flavonoids in isolated mitochondria. Phytother Res 2008 Sep;22(9):1213-8.
  6. Ealey KN, El-Sohemy A, Archer MC. Effects of dietary conjugated linoleic acid on the expression of uncoupling proteins in mice and rats. Lipids 2002 Sep;37(9):853-61.
  7. Kidd PM. Neurodegeneration from mitochondrial insufficiency: nutrients, stem cells, growth factors, and prospects for brain rebuilding using integrative management. Altern Med Rev 2005 Dec;10(4):268-93.
  8. Page MM, Robb EL, Salway KD, Stuart JA. Mitochondrial redox metabolism: aging, longevity and dietary effects. Mech Ageing Dev 2010 Apr;131(4):242-52.
  9. Babizhayev MA, Yegorov YE. Telomere attrition in lens epithelial cells—a target for N-acetylcarnosine therapy. Front Biosci 2010 Jun 1;15:934-56.

Will Block is the publisher and editorial director of Life Enhancement magazine.

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