More than 300 different theories have been posited to explain the nature (mechanisms) and causes (reasons for natural emergence or factors) of aging. Good
theories would both explain past observations and predict the results of future experiments. Some of the theories may complement each other, overlap, contradict, or may not preclude various other theories. Theories of aging fall into two broad categories: evolutionary theories of aging and mechanistic theories of aging. Evolutionary theories of aging primarily explain why aging happens, but do not concern themselves with the molecular mechanism(s) that drive the process. All evolutionary theories of aging rest on the basic mechanisms that the force of natural selection declines with age. Mechanistic theories of aging can be divided into theories that propose aging is programmed, and damage accumulation theories, i.e. those that propose aging to be caused by specific molecular changes occurring over time.
Evolutionary aging theories Antagonistic pleiotropy One theory was proposed by
George C. Williams The theory suggests that aging occurs due to a strategy in which an individual only invests in maintenance of the soma for as long as it has a realistic chance of survival. A species that uses resources more efficiently will live longer, and therefore be able to pass on genetic information to the next generation. The demands of reproduction are high, so less effort is invested in the repair and maintenance of somatic cells, compared to
germline cells, to focus on reproduction and species survival.
Programmed aging theories Programmed theories of aging posit that aging is adaptive, normally invoking selection for
evolvability or
group selection. The
reproductive-cell cycle theory suggests that aging is regulated by changes in hormonal signaling over the lifespan.
Damage accumulation theories The free radical theory of aging One of the most prominent theories of aging was first proposed by Harman in 1956. It posits that
free radicals produced by dissolved oxygen, radiation, cellular respiration, and other sources cause damage to the molecular machines in the cell and gradually wear them down. This is also known as
oxidative stress. There is substantial evidence to back up this theory. Old animals have larger amounts of oxidized proteins, DNA, and lipids than their younger counterparts.
Chemical damage woman photographed by
Edward S. Curtis in 1924 One of the earliest aging theories was the
Rate of Living Hypothesis described by
Raymond Pearl in 1928 (based on earlier work by
Max Rubner), which states that fast
basal metabolic rate corresponds to short
maximum life span. While there may be some validity to the idea that for various types of specific damage detailed below that are by-products of
metabolism, all other things being equal, a fast metabolism may reduce lifespan, in general this theory does not adequately explain the differences in lifespan either within, or between, species.
Calorically restricted animals process as much, or more, calories per gram of body mass, as their
ad libitum fed counterparts, yet exhibit substantially longer lifespans. Similarly, metabolic rate is a poor predictor of lifespan for birds, bats and other species that, it is presumed, have reduced mortality from predation, and therefore have evolved long lifespans even in the presence of very high metabolic rates. In a 2007 analysis it was shown that, when modern statistical methods for correcting for the effects of body size and
phylogeny are employed, metabolic rate does not correlate with
longevity in mammals or birds. Concerning specific types of chemical damage caused by metabolism, it is suggested that damage to long-lived
biopolymers, such as structural
proteins or
DNA, caused by ubiquitous chemical agents in the body such as
oxygen and
sugars, are in part responsible for aging. The damage can include breakage of biopolymer chains,
cross-linking of biopolymers, or chemical attachment of unnatural substituents (
haptens) to biopolymers. Under normal
aerobic conditions, approximately 4% of the
oxygen metabolized by
mitochondria is converted to
superoxide ion, which can subsequently be converted to
hydrogen peroxide,
hydroxyl radical and eventually other reactive species including other
peroxides and
singlet oxygen, which can, in turn, generate
free radicals capable of damaging structural proteins and DNA. and
tea. However their typically positive effects on lifespans when consumption is moderate have also been explained by effects on
autophagy,
glucose metabolism and
AMPK.
Sugars such as
glucose and
fructose can react with certain
amino acids such as
lysine and
arginine and certain DNA bases such as
guanine to produce sugar adducts, in a process called
glycation. These adducts can further rearrange to form reactive species, which can then cross-link the structural proteins or DNA to similar biopolymers or other biomolecules such as non-structural proteins. People with
diabetes, who have elevated
blood sugar, develop senescence-associated disorders much earlier than the general population, but can delay such disorders by rigorous control of their blood sugar levels. There is evidence that sugar damage is linked to oxidant damage in a process termed
glycoxidation.
Free radicals can damage proteins,
lipids or
DNA.
Glycation mainly damages proteins. Damaged proteins and lipids accumulate in
lysosomes as
lipofuscin. Chemical damage to structural proteins can lead to loss of function; for example, damage to
collagen of
blood vessel walls can lead to vessel-wall stiffness and, thus,
hypertension, and vessel wall thickening and reactive tissue formation (
atherosclerosis); similar processes in the
kidney can lead to
kidney failure. Damage to
enzymes reduces cellular functionality. Lipid
peroxidation of the inner
mitochondrial membrane reduces the
electric potential and the ability to generate energy. It is probably no accident that nearly all of the so-called "
accelerated aging diseases" are due to defective
DNA repair enzymes. It is believed that the
impact of alcohol on aging can be partly explained by alcohol's activation of the
HPA axis, which stimulates
glucocorticoid secretion, long-term exposure to which produces symptoms of aging.
DNA damage DNA damage was proposed in a 2021 review to be the underlying cause of aging because of the mechanistic link of DNA damage to nearly every aspect of the aging phenotype. Slower rate of accumulation of
DNA damage as measured by the DNA damage marker gamma H2AX in leukocytes was found to correlate with longer lifespans in comparisons of
dolphins,
goats,
reindeer,
American flamingos and
griffon vultures. DNA damage-induced
epigenetic alterations, such as
DNA methylation and many
histone modifications, appear to be of particular importance to the aging process.
Mutation accumulation Natural selection can support lethal and harmful
alleles, if their effects are felt after reproduction. The geneticist
J. B. S. Haldane wondered why the dominant mutation that causes
Huntington's disease remained in the population, and why natural selection had not eliminated it. The onset of this neurological disease is (on average) at age 45 and is invariably fatal within 10–20 years. Haldane assumed that, in human prehistory, few survived until age 45. Since few were alive at older ages and their contribution to the next generation was therefore small relative to the large cohorts of younger age groups, the force of selection against such late-acting deleterious mutations was correspondingly small. Therefore, a
genetic load of late-acting deleterious mutations could be substantial at
mutation–selection balance. This concept came to be known as the
selection shadow.
Peter Medawar formalised this observation in his
mutation accumulation theory of aging. "The force of natural selection weakens with increasing age—even in a theoretically immortal population, provided only that it is exposed to real hazards of mortality. If a genetic disaster... happens late enough in individual life, its consequences may be completely unimportant". Age-independent hazards such as predation, disease, and accidents, called '
extrinsic mortality', mean that even a population with
negligible senescence will have fewer individuals alive in older age groups.
Other damage A study concluded that
retroviruses in the
human genomes can become awakened from dormant states and contribute to aging which can be blocked by
neutralizing antibodies, alleviating "cellular senescence and tissue degeneration and, to some extent, organismal aging".
Stem cell theories of aging ;Hematopoietic stem cell aging ;Hematopoietic stem cell diversity aging ;Hematopoietic mosaic loss of chromosome Y ==Biomarkers of aging==