Summary: The founder of the free radical theory of aging summarising the results that back the theory, some nice graphs, and other interesting bits of speculation.
Interestingness: 6
Paper by Denham Harman, MD, PhD, in the Journal of Anti-Aging Medicine, Volume 2, Issue 1, Spring 1999.
(((This is a summary of the current state of the free radical theory of aging (FRTA) by the guy that is introduced as the father of the FRTA. I didn't like the way it was written. I'm going to skip big chunks of it)))
(((The paper starts with a series of mortality curves over age across time for women in Sweden from the 1750s to 1992. These are cool, even if I've seen them before. They show the mortality following Gompertz function with mortality going up exponentially after around age 50 with a doubling time of about 7 years. The slope of this exponential is the same in all curves. While mortality is much lower across all ages as we get closer to the present, the line goes exponential at a younger and younger age, so that the difference in mortality at ages 70 onwards is not that big across history. So, for example, the curve for the 1900s and 1920s seem to hit the exponential proper only at age 60, while the curve for 1992 seems to be on the exponential from age 40. The left hand side of the curves, that is, the bits before we hit the exponential growth, have declined massively across history. The text mentions that in that 1992 curve, only 1.1% of all females in Sweden die before age 28 (the date at which he puts the exponential rise starting) )))
(((It continues with a couple of life expectancy graphs from the 1950s to the present for male and females in Sweden, Switzerland, the USA and Japan. The first three going up by 1-2 years per decade and Japan by 3 years per decade, from a lower base. I don't really understand what these graphs or the previous mortality curves have to do with the main theme of the article, but I like them anyway)))
The free radical theory of aging (FRTA) says that all aging and death in all living things is based on the initiation of free radical reactions, the rate of which is determined by genetics and environment. This theory was later extended (((modified?))) to say that in mitochondria-containing living things, it is the rate of initiation of free radical reactions (FRR) in the mitochondria that determines their lifespan. FRRs can be classified into initiation, a propagation chain, and termination. An antioxidant usually refers to a compound that breaks the propagation chain, or, in general, any substance that delays or inhibits oxidation in low concentrations.
The major sources of radical reactions are:
- Respiratory chain
- Phagocytosis
- Prostaglandin synthesis
- Cytochrome P-450 system
- Nonenzymatic reactions of O2
- Ionising radiation
Defenses against damage caused by FRR are:
- Antioxidants. eg: tocopherols, carotenes
- Heme-containing peroxidases. eg: catalase
- Glutathione peroxidase
- Superoxide dismutases (SOD)
- DNA repair mechanisms
By the FRTA, slowing down FRRs would increase longevity. Studies backing this up include:
- Overexpression of superoxide dismutase and catalase in fruit flies extended life span by a third.
- Longer-lived strains of fruit flies, flatworms and bread mold have higher antioxidant enzyme activity than short-lived strains
- Addition of 2-mercaptoethylamine (2-MEA), an antioxidant, to food increased average lifespan of LAF1 mice by 29.2% (((no idea what the characteristics of LAF1 mice are)))
- 2-MEA addition to food of mice mothers before mating increased lifespan of their offsprings by 15% and 8% to male and female offsprings respectively
Decreasing initiation rates of endogenous FRRs would also lead to increased longevity. The rate can be reduced by caloric reduction, compounds that compete with O2 for access to electron-rich areas of the mitochondria, compounds that bind to the respiratory chain and stop the reaction with O2, and genetic regulation of mitochondrial superoxide creation. Cutting caloric intake of rats by 40% increased average lifespan by 40% and maximal life span by 49% (((Those numbers are higher than I'm usually accustomed to))). The study also suggests a lower rate of aging for rats under caloric restriction (((ie a lower gradient on the semilog plot of age vs mortality))) (((I think the suggested link is lower amount of products to oxidise => lower total load of FRR in mitochondria))).
Only study showing antioxidant to extend maximal lifespan of mice is 2-MEA, added at 0.25% w/w to the diet of BC3F mice extended mean and maximal lifespan by 13% and 12% respectively. The study hasn't been replicated. The reason that most antioxidants fail to extend lifepan is that they have toxic effects on mitochondria at lower concentrations than those needed to slow down FRRs significantly.
The paper continues by listing the possible effects of the FRTA on specific diseases. They are:
- Cancer, listing epidemiological studies suggesting vitamin C and fruits and vegetables having lower incidence
- Atherosclerosis, caused by lesions that would result in higher localised concentrations of oxidation products, and oxidation of polyunsaturatid lipids, and mentioning a study of vitamin E supplementation showing a decrease of 40% in coronary artery disease (((never heard of that one. will have to look it up)))
- Hypertension, mentioning a study of SOD targeted to endothelium cells lowering blood pressure in spontaneously hypertensive rats, but not in normal rats
- Alzheimer's disease, listing mutations in mtDNA, mutations in amyloid precursor protein (APP), and increases in levels of APP and SOD in Down's syndrome (((I don't get how the last two are meant to relate to FRTA)))
- Immune deficiency, saying some antioxidants increase immune responses
- Autoimmunity, with ethoxyquin fed to a mice used for studying autoimmune disease (NZB) increasing lifespan by 32%
The gender mortality gap is also supposedly explained by the FRTA via two different effects: one is the lower stores of iron in women prior to menopause leading to less FRRs catalysed by iron, and the second (((something I don't even understand enough to describe))).
The paper finishes by claiming that a large part of the increase in lifespan in the USA since the 1960s could be attributable to the widespread use of multi-vitamins by the population (((yeah riiiiiight))).
Abstract follows:
Aging is the accumulation of changes that increase the risk of death. The major contributors after age 28 years are the endogenous chemical reactions that, collectively, produce aging changes that exponentially increase the chances for disease and death with age. These reactions constitute the "inborn aging process." This process is the major risk factor for disease and death of the 98% to 99% of cohorts still alive at age 28 in developed countries, where living conditions are now near optimum.
The Free Radical Theory of Aging (FRTA) and, simultaneously, the discovery of the ubiquitous, important involvement of endogenous free radical reactions in the metabolism of biologic systems, arose in 1954 from a consideration of aging phenomena from the premise that a single common process, modifiable by genetic and environmental factors, was responsible for the aging and death of all living things. The FRTA postulates that the single common process is the initiation of free radical reactions. These reactions, however initiated, could be responsible for the progressive deterioration of biologic systems with time because of their inherent ability to produce random change. The theory was extended in 1972 with the suggestion that the life span was largely determined by the rate of free radical damage to the mitochondria.
The FRTA suggests the possibility that measures to decrease the rate of initiation and/or the chain length of free radical reactions may, at least in some cases, decrease the rate of reactions that produce aging changes without significantly depressing those involved in maintenance and function. Many studies support this possibility.
Applications of the FRTA have been fruitful. For example, it is a useful guide to efforts to increase the life span, and it provides plausible explanations for the aging phenomenon (e.g., the association of disease with age as well as insight into pathogenesis; the gender gap; the association between events in early life and late onset disease; and the shortening of telomeres with cell division). Further, it is reasonable to expect on the basis of animal and epidemiologic studies that the increasing population-wide use of antioxidant supplements and ingestion of foods high in antioxidant capacity over the past 40 years have helped to increase the functional life span of the population by contributing significantly to the decline in "free radical" diseases, to increases in the fraction of elderly, and to the decline in chronic disability in this group.
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