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Tuesday, September 2, 2025

Senescence

From Wikipedia, the free encyclopedia

Senescence (/ˌsɪˈnɛsəns/) or biological aging is the gradual deterioration of functional characteristics in living organisms. Whole organism senescence involves an increase in death rates or a decrease in fecundity with increasing age, at least in the later part of an organism's life cycle. However, the effects of senescence can be delayed. The 1934 discovery that calorie restriction can extend lifespans by 50% in rats, the existence of species having negligible senescence, and the existence of potentially immortal organisms such as members of the genus Hydra have motivated research into delaying senescence and thus age-related diseases. Rare human mutations can cause accelerated aging diseases.

Environmental factors may affect aging – for example, overexposure to ultraviolet radiation accelerates skin aging. Different parts of the body may age at different rates and distinctly, including the brain, the cardiovascular system, and muscle. Similarly, functions may distinctly decline with aging, including movement control and memory. Two organisms of the same species can also age at different rates, making biological aging and chronological aging distinct concepts.

Definition and characteristics

Organismal senescence is the aging of whole organisms. Actuarial senescence can be defined as an increase in mortality or a decrease in fecundity with age. The Gompertz–Makeham law of mortality says that the age-dependent component of the mortality rate increases exponentially with age.

Aging is characterized by the declining ability to respond to stress, increased homeostatic imbalance, and increased risk of aging-associated diseases, including cancer and heart disease. Aging has been defined as "a progressive deterioration of physiological function, an intrinsic age-related process of loss of viability and increase in vulnerability."

In 2013, a group of scientists defined nine hallmarks of aging that are common between organisms with emphasis on mammals:

In a decadal update, three hallmarks have been added, totaling 12 proposed hallmarks:

The environment induces damage at various levels, e.g., damage to DNA, and damage to tissues and cells by oxygen radicals (widely known as free radicals), and some of this damage is not repaired and thus accumulates with time. Cloning from somatic cells rather than germ cells may begin life with a higher initial load of damage. Dolly the sheep died young from a contagious lung disease, but data on an entire population of cloned individuals would be necessary to measure mortality rates and quantify aging.

The evolutionary theorist George Williams wrote, "It is remarkable that after a seemingly miraculous feat of morphogenesis, a complex metazoan should be unable to perform the much simpler task of merely maintaining what is already formed."

Variation among species

Different speeds with which mortality increases with age correspond to different maximum life span among species. For example, a mouse is elderly at 3 years, a human is elderly at 80 years, and ginkgo trees show little effect of age even at 667 years.

Almost all organisms senesce, including bacteria which have asymmetries between "mother" and "daughter" cells upon cell division, with the mother cell experiencing aging, while the daughter is rejuvenated. There is negligible senescence in some groups, such as the genus HydraPlanarian flatworms have "apparently limitless telomere regenerative capacity fueled by a population of highly proliferative adult stem cells." These planarians are not biologically immortal, but rather their death rate slowly increases with age. Organisms that are thought to be biologically immortal would, in one instance, be Turritopsis dohrnii, also known as the "immortal jellyfish", due to its ability to revert to its youth when it undergoes stress during adulthood. The reproductive system is observed to remain intact, and even the gonads of Turritopsis dohrnii exist.

Some species exhibit "negative senescence", in which reproduction capability increases or is stable, and mortality falls with age, resulting from the advantages of increased body size during aging.

Theories of aging

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.

The aging process can be explained with different theories. These are evolutionary theories, molecular theories, system theories and cellular theories. The evolutionary theory of ageing was first proposed in the late 1940s and can be explained briefly by the accumulation of mutations (evolution of ageing), disposable soma and antagonistic pleiotropy hypothesis. The molecular theories of ageing include phenomena such as gene regulation (gene expression), codon restriction, error catastrophe, somatic mutation, accumulation of genetic material (DNA) damage (DNA damage theory of aging) and dysdifferentiation. The system theories include the immunologic approach to ageing, rate-of-living and the alterations in neuroendocrinal control mechanisms. (See homeostasis). Cellular theory of ageing can be categorized as telomere theory, free radical theory (free-radical theory of aging) and apoptosis. The stem cell theory of aging is also a sub-category of cellular theories.

Evolutionary aging theories

Antagonistic pleiotropy

One theory was proposed by George C. Williams and involves antagonistic pleiotropy. A single gene may affect multiple traits. Some traits that increase fitness early in life may also have negative effects later in life. But, because many more individuals are alive at young ages than at old ages, even small positive effects early can be strongly selected for, and large negative effects later may be very weakly selected against. Williams suggested the following example: Perhaps a gene codes for calcium deposition in bones, which promotes juvenile survival and will therefore be favored by natural selection; however, this same gene promotes calcium deposition in the arteries, causing negative atherosclerotic effects in old age. Thus, harmful biological changes in old age may result from selection for pleiotropic genes that are beneficial early in life but harmful later on. In this case, selection pressure is relatively high when Fisher's reproductive value is high and relatively low when Fisher's reproductive value is low.

Cancer versus cellular senescence tradeoff theory of aging

Senescent cells within a multicellular organism can be purged by competition between cells, but this increases the risk of cancer. This leads to an inescapable dilemma between two possibilities—the accumulation of physiologically useless senescent cells and cancer, both of which lead to increasing rates of mortality with age.

Disposable soma

The disposable soma theory of aging was proposed by Thomas Kirkwood in 1977. 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

Elderly Klamath 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. Certain metal ions found in the body, such as copper and iron, may participate in the process. (In Wilson's disease, a hereditary defect that causes the body to retain copper, some of the symptoms resemble accelerated senescence.) These processes termed oxidative stress are linked to the potential benefits of dietary polyphenol antioxidants, for example in coffee, and tea. However their typically positive effects on lifespans when consumption is moderate have also been explained by effects on autophagyglucose 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. Evidence for the theory that DNA damage is the fundamental cause of aging was first reviewed in 1981.

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

The stem cell theory of aging postulates that the aging process is the result of the inability of various types of stem cells to continue to replenish the tissues of an organism with functional differentiated cells capable of maintaining that tissue's (or organ's) original function. Damage and error accumulation in genetic material is always a problem for systems regardless of the age. The number of stem cells in young people is very much higher than older people and thus creates a better and more efficient replacement mechanism in the young contrary to the old. In other words, aging is not a matter of the increase in damage, but a matter of failure to replace it due to a decreased number of stem cells. Stem cells decrease in number and tend to lose the ability to differentiate into progenies or lymphoid lineages and myeloid lineages.

Maintaining the dynamic balance of stem cell pools requires several conditions. Balancing proliferation and quiescence along with homing (See niche) and self-renewal of hematopoietic stem cells are favoring elements of stem cell pool maintenance while differentiation, mobilization and senescence are detrimental elements. These detrimental effects will eventually cause apoptosis.

There are also several challenges when it comes to therapeutic use of stem cells and their ability to replenish organs and tissues. First, different cells may have different lifespans even though they originate from the same stem cells (See T-cells and erythrocytes), meaning that aging can occur differently in cells that have longer lifespans as opposed to the ones with shorter lifespans. Also, continual effort to replace the somatic cells may cause exhaustion of stem cells.
Hematopoietic stem cell aging
Hematopoietic stem cells (HSCs) regenerate the blood system throughout life and maintain homeostasis. DNA strand breaks accumulate in long term HSCs during aging. This accumulation is associated with a broad attenuation of DNA repair and response pathways that depends on HSC quiescence. DNA ligase 4 (Lig4) has a highly specific role in the repair of double-strand breaks by non-homologous end joining (NHEJ). Lig4 deficiency in the mouse causes a progressive loss of HSCs during aging. These findings suggest that NHEJ is a key determinant of the ability of HSCs to maintain themselves over time.
Hematopoietic stem cell diversity aging
A study showed that the clonal diversity of stem cells that produce blood cells gets drastically reduced around age 70 to a faster-growing few, substantiating a novel theory of ageing which could enable healthy aging.
Hematopoietic mosaic loss of chromosome Y
A 2022 study showed that blood cells' loss of the Y chromosome in a subset of cells, called 'mosaic loss of chromosome Y' (mLOY) and reportedly affecting at least 40% of 70 years-old men to some degree, contributes to fibrosis, heart risks, and mortality in a causal way.

Biomarkers of aging

If different individuals age at different rates, then fecundity, mortality, and functional capacity might be better predicted by biomarkers than by chronological age. However, graying of hairface aging, skin wrinkles, and other common changes seen with aging are not better indicators of future functionality than chronological age. Biogerontologists have continued efforts to find and validate biomarkers of aging, but success thus far has been limited.

Levels of CD4 and CD8 memory T cells and naive T cells have been used to give good predictions of the expected lifespan of middle-aged mice.

Aging clocks

There is interest in an epigenetic clock as a biomarker of aging, based on its ability to predict human chronological age. Basic blood biochemistry and cell counts can also be used to accurately predict the chronological age. It is also possible to predict the human chronological age using transcriptomic aging clocks.

There is research and development of further biomarkers, detection systems, and software systems to measure the biological age of different tissues or systems or overall. For example, a deep learning (DL) software using anatomic magnetic resonance images estimated brain age with relatively high accuracy, including detecting early signs of Alzheimer's disease and varying neuroanatomical patterns of neurological aging, and a DL tool was reported as to calculate a person's inflammatory age based on patterns of systemic age-related inflammation.

Aging clocks have been used to evaluate the impacts of interventions on humans, including combination therapies. Employing aging clocks to identify and evaluate longevity interventions represents a fundamental goal in aging biology research. However, achieving this goal requires overcoming numerous challenges and implementing additional validation steps.

Genetic determinants of aging

Several genetic components of aging have been identified using model organisms, ranging from the simple budding yeast Saccharomyces cerevisiae to worms such as Caenorhabditis elegans and fruit flies (Drosophila melanogaster). Study of these organisms has revealed the presence of at least two conserved aging pathways.

Gene expression is imperfectly controlled, and random fluctuations in the expression levels of many genes may contribute to the aging process, as suggested by a study of such genes in yeast. Individual cells, which are genetically identical, nonetheless can have substantially different responses to outside stimuli, and markedly different lifespans, indicating the epigenetic factors play an important role in gene expression and aging as well as genetic factors. There is research into epigenetics of aging.

The ability to repair DNA double-strand breaks declines with aging in mice and humans.

A set of rare hereditary (genetics) disorders, each called progeria, has been known for some time. Sufferers exhibit symptoms resembling accelerated aging, including wrinkled skin. The cause of Hutchinson–Gilford progeria syndrome was reported in the journal Nature in May 2003. This report suggests that DNA damage, not oxidative stress, is the cause of this form of accelerated aging.

A study indicates that aging may shift activity toward short genes or shorter transcript length and that this can be countered by interventions.

Healthspans and aging in society

Past and projected age of the human world population through time as of 2021
Healthspan-lifespan gap (LHG)
Healthspan extension relies on the unison of social, clinical and scientific programs or domains of work.

Healthspan can broadly be defined as the period of one's life that one is healthy, such as free of significant diseases or declines of capacities (e.g., of senses, muscle, endurance and cognition).

With aging populations, there is a rise of age-related diseases which puts major burdens on healthcare systems as well as contemporary economies or contemporary economics and their appendant societal systems. Healthspan extension and anti-aging research seek to extend the span of health in the old as well as slow aging or its negative impacts such as physical and mental decline. Modern anti-senescent and regenerative technology with augmented decision making could help "responsibly bridge the healthspan-lifespan gap for a future of equitable global wellbeing". Aging is "the most prevalent risk factor for chronic disease, frailty and disability, and it is estimated that there will be over 2 billion persons age > 60 by the year 2050", making it a large global health challenge that demands substantial (and well-orchestrated or efficient) efforts, including interventions that alter and target the inborn aging process.

Biological aging or the LHG comes with a great cost burden to society, including potentially rising health care costs (also depending on types and costs of treatments). This, along with global quality of life or wellbeing, highlight the importance of extending healthspans.

Many measures that may extend lifespans may simultaneously also extend healthspans, albeit that is not necessarily the case, indicating that "lifespan can no longer be the sole parameter of interest" in related research. While recent life expectancy increases were not followed by "parallel" healthspan expansion, awareness of the concept and issues of healthspan lags as of 2017. Scientists have noted that "[c]hronic diseases of aging are increasing and are inflicting untold costs on human quality of life".

Interventions

Life extension is the concept of extending the human lifespan, either modestly through improvements in medicine or dramatically by increasing the maximum lifespan beyond its generally-settled biological limit of around 125 years. Several researchers in the area, along with "life extensionists", "immortalists", or "longevists" (those who wish to achieve longer lives themselves), postulate that future breakthroughs in tissue rejuvenation, stem cells, regenerative medicine, molecular repair, gene therapy, pharmaceuticals, and organ replacement (such as with artificial organs or xenotransplantations) will eventually enable humans to have indefinite lifespans through complete rejuvenation to a healthy youthful condition (agerasia). The ethical ramifications, if life extension becomes a possibility, are debated by bioethicists.

The sale of purported anti-aging products such as supplements and hormone replacement is a lucrative global industry. For example, the industry that promotes the use of hormones as a treatment for consumers to slow or reverse the aging process in the US market generated about $50 billion of revenue a year in 2009. The use of such hormone products has not been proven to be effective or safe. Similarly, a variety of apps make claims to assist in extending the life of their users, or predicting their lifespans.

Anti-aging movement

From Wikipedia, the free encyclopedia

The anti-aging movement is a social movement devoted to eliminating or reversing aging, or reducing the effects of it. A substantial portion of the attention of the movement is on the possibilities for life extension, but there is also interest in techniques such as cosmetic surgery which ameliorate the effects of aging rather than delay or defeat it.

There are numerous scientists of this movement with different approaches. Two of the most popular proponents of the anti-aging movement include Ray Kurzweil, who says humanity can defeat aging through the advance of technology, allowing us to reach the longevity escape velocity, and Aubrey de Grey, who says that the human body is a very complicated machine and, thus, can be repaired indefinitely. Other scientists and significant contributors to the movement include molecular biologists, geneticists, and biomedical gerontologists such as Gary Ruvkun, Cynthia Kenyon, and Arthur D. Levinson. However, figures in the gerontology community in 2003 tried to distance their research from the perceived pseudoscience of the movement.

Anti-aging medicine

Anti-aging medicine has become a budding and rapidly growing medical specialty as physicians who initially sought treatment for themselves have received training and certification in its practice by organizations such as the American Academy of Anti-Aging Medicine (A4M) co-founded by Dr Robert M. Goldman and Ronald Klatz.

Human growth hormone

Central to anti-aging medicine is administration of human growth hormone. Clinical studies have shown that low-dose growth hormone (GH) treatment for adults with GH deficiency changes the body composition by increasing muscle mass, decreasing fat mass, and increasing bone density and muscle strength. It also improves cardiovascular parameters (i.e. decrease of LDL cholesterol) and affects the quality of life without significant side effects. However, it is also said to have potentially dangerous side effects when used in injectable form if proper protocols are not followed. It is not approved for use in healthy aging patients, though the restriction is occasionally sidestepped by means of a diagnosis of some injury, organic condition, or adult-growth-hormone deficiency which may have resulted in reduced secretion of the hormone.

Menopausal hormone drugs

Administration of estrogen and other hormones such as progestin were popularized by the 1966 book Feminine Forever by Robert A. Wilson. However, the increase of the use of estrogen was shown to be associated with an increased risk of cancer. Later, in 2002, research into the long-term effects of estrogen on post-menopausal women, the Women's Health Initiative, produced evidence that there were serious side effects. Physicians who prescribe the hormones now prescribe low doses of the drugs. Research into the long-term effects of hormone replacement therapy is continuing, with a 2017 Cochrane systematic review concluding that long-term use may decrease the risk of bone fractures or postmenopausal osteoporosis, but increase the risk of stroke, heart attacks, endometrial cancer, and breast cancer. Hormone therapy is generally only recommended for postmenopausal women who are at a high risk of osteoporosis when non-hormonal treatments are not suitable. Hormone therapy is not suitable or advised for treating cardiovascular disease, dementia, or for preventing cognitive decline in postmenopausal women. The risks of long-term hormonal therapy for women under 50 years of age have not been determined.

Senolytics

A senolytic (from the words senescence and -lytic, "destroying") is among a class of small molecules under basic research to determine if they can selectively induce death of senescent cells and improve health in humans. A goal of this research is to discover or develop agents to delay, prevent, alleviate, or reverse age-related diseases. Removal of senescent cells with senolytics has been proposed as a method of enhancing immunity during aging.

A related concept is "senostatic", which means to suppress senescence.

Scientific approaches

Biogerontology is a scientific discipline which has the same area of interest but, as a branch of gerontology, takes a more conservative approach. Caloric restriction is a phenomenon introduced in anti-aging techniques which focuses on depletion of calories and taking the right amount of nutrients necessary for growth.

Calorie restriction

Calorie restriction (CR) refers to a dietary restriction that focuses on less calorie intake to increase longevity and reduce age-related disease in humans. Calorie restriction maintains a low calorie intake that helps to regulate the rate of aging and increases the youthfulness of an individual or animal. Low calorie intake has directly been correlated to negative energy balance which promotes low body mass index (BMI) and comparatively high plasma dehydroepiandrosterone (DHEA) for improved life expectancy. Calorie restriction has widely been practiced by pregnant women and people with pre-existing medical conditions such as diabetes. The right amount of calorie restriction help pregnant women to achieve positive weight gain whereas a significant drop in calorie intake can lead to hypothalamic alterations leading to long-term effects in the offspring. Moderate CR in diabetic patients increases insulin sensitivity and reduces the amount of hepatic fat in obese individual and type 2 diabetes. Long term CR in older animals results in stem cell function similar to that of the younger groups. The active stem cell function helps in enhanced recovery of the damaged skeletal muscle tissue, which is slower in older individuals compared to younger individuals. CR in the United States has shown a prolonged life span in women compared to men as women tend to consume 25% fewer calories than men in their lifetime. The statistical analysis of CR available for anti-aging movement in humans is insufficient to prove the prolonged lifespan associated with CR.

Mass movement

A substantial fraction of older people, taking their cue from alternative medicine, purchase and use herbal supplements and other products which promise relief from the incidents and dangers of aging. However, many such products are unregulated, and can instead pose serious health risks.

Reception

There are at least two opposite views on the prospects of anti-aging research and development. One view is that there is a great deal of over-heated rhetoric in use with respect to life extension with over-optimistic projections by its advocates. They also claim that there is little evidence that any significant breakthrough has been made, or is on the horizon. Some state that this is largely due to a current lack of funding or interest in the issue. A study of the commonly used supplements and hormone treatments published in 2006 in the Cleveland Clinic Journal of Medicine showed that none of them are effective for extending life. Another view is noticing that recent scientific successes in rejuvenation and extending the lifespan of model animals and discovery of a variety of species (including humans of advanced ages) having negligible senescence give hope to achieve negligible senescence (cancel aging) for younger humans, reverse ageing, or at least significantly delay it.

Though some scientists think curing aging is impossible, there are some criticisms of both the time frame life extensionists envision (the first, perhaps somewhat crude, treatments within the next several decades, or at least before the beginning of the 22nd century) and of whether curing aging is even desirable. Common criticisms of the idea of life extension are fears it will cause the world to be more overpopulated; however, de Grey counters that by saying that since menopause would also be delayed, women could wait longer to have children and, thus, the rate of growth would actually decline as a result. Also, the slowly growing population would buy centuries of time to figure out new places to live, such as space colonies.

Evolution of ageing

From Wikipedia, the free encyclopedia

Enquiry into the evolution of ageing, or aging, aims to explain why a detrimental process such as ageing would evolve, and why there is so much variability in the lifespans of organisms. The classical theories of evolution (mutation accumulation, antagonistic pleiotropy, and disposable soma) suggest that environmental factors, such as predation, accidents, disease, and/or starvation, ensure that most organisms living in natural settings will not live until old age, and so there will be very little pressure to conserve genetic changes that increase longevity. Natural selection will instead strongly favor genes which ensure early maturation and rapid reproduction, and the selection for genetic traits which promote molecular and cellular self-maintenance will decline with age for most organisms.

Theories and hypotheses

The beginning

August Weismann was responsible for interpreting and formalizing the mechanisms of Darwinian evolution in a modern theoretical framework. In 1889, he theorized that ageing was part of life's program to make room for the next generation in order to sustain the turnover that is necessary for evolution. The idea that the ageing characteristic was selected (an adaptation) because of its deleterious effect was largely discounted for much of the 20th century, but a theoretical model suggests that altruistic ageing could evolve if there is little migration among populations. Weismann later abandoned his theory and after some time followed up with his "programmed death" theory.

Natural selection is a process that allows organisms to better adapt to the environment, it is the survival of the fittest which are predicted to produce more offsprings. Natural selection acts on life history traits in order to optimize reproductive success and lifetime fitness. Fitness in this context refers to how likely an organism is to survive and reproduce. It is based on the environment and is also relative to other individuals in the population. Examples of life history traits include; age and size at first reproduction, number of size and offsprings produced, and the period of reproductive lifespan. Organisms put energy into growth, reproduction, and maintenance by following a particular pattern which changes throughout their lifetime due to the trade-offs that exist between the different energy allocations. Investment in current vs future reproduction, for example, comes at the expense of the other. Natural selection, however is not so effective on organisms as they age. Mutation accumulation (MA) and antagonistic pleiotropy (AP) are two factors which contribute to senescence. Both MA, and AP contribute to age-related declines in fitness. The accumulation of random, germline age-related mutated alleles is known as mutation accumulation. Note that somatic mutations are not heritable, they are only a source of developmental variation. Studies done on Drosophila melanogaster have shown that mutation accumulation drives the combination of alleles which have "age-specific additive effects" that cause a decline in stress response and ultimately an age-related decline in fitness. The number of germ cell divisions per generation is variable among lineages, and relates to genome size; for humans; 401 germ cell divisions occur per generation in males and 31 in females.

Mutation accumulation

Germ line

The first modern theory of mammal ageing was formulated by Peter Medawar in 1952. This theory formed in the previous decade with J. B. S. Haldane and his selection shadow concept. The development of human civilization has shifted the selective shadow as the conditions that humans now live in include improved quality of food, living conditions, and healthcare. This improved healthcare includes modern medicine such as antibiotics and new medical technology. A few studies in Drosophila have shown that the age of expression of novel deleterious mutations, defines the effects they contribute on mortality. Overall, however; although their frequency increases, their effects and variation decreases with age.

There is no theory that explains how these deleterious mutations affect fitness on different ages and the evolution of senescence. Their idea was that ageing was a matter of neglect, as nature is a highly competitive place. Almost all animals die in the wild from predators, disease, or accidents, which lowers the average age of death. Therefore, there is not much reason why the body should remain fit for the long haul because selection pressure is low for traits that would maintain viability past the time when most animals would have died anyway. Metabolic diseases come along due to the low demand for physical activity in modern civilization compared to times where humans had to forage in the wild for survival. With the selective shadow now shifted, humans must deal with these new selective pressures.

Senescence is considered a by-product of physiology because our cell metabolism creates products that are toxic, we get mutations when we age, and we don't have enough stem cells that regenerate. Why did selection not find and favor mutations in ways that allow us, for example, to regenerate our cells, or to not produce toxic metabolism? Why did menopause evolve? Because selection is more efficient on traits that appear early in life. Mutations that have an effect early in life will increase fitness much more than mutations that manifest late. Most people have already reproduced before any disease manifest; this means that parents will pass their alleles to their offsprings before they show any fitness problems, and it is therefore "too late" for selection.

The two theories; non-adaptive, and adaptive, are used to explain the evolution of senescence, which is the decline in reproduction with age. The non-adaptive theory assumes that the evolutionary deterioration of human age occurs as a result of accumulation of deleterious mutations in the germline. These deleterious mutations start expressing themselves late in life, by the time we are weak/wobbly and have already reproduced, this means that Natural selection cannot act on them because reproduction has ended. Studies done on Drosophila melanogaster have shown an inverse relationship between the mean optimal age at maturity and mutation rates per gene. Mutation accumulation affects the allocation of energy, and time that are directed towards growth and reproduction over the lifetime of an organism, especially the period of reproductive lifespan due to the fact that mutation accumulation accelerates senescence, this means that organisms must reach the optimum age of maturity at a younger age as their reproductive lifespan is shortened with accumulated mutation.

Mutations happen, and they are completely random with respect to a need in the environment and fitness. Mutations can either be beneficial in which they increase an organism's fitness, neutral in which they do not affect an organism's fitness or deleterious where they negatively affect an organism's fitness. Previously done experiments have shown that most mutation accumulations are deleterious, and just a few are beneficial. Mutations of genes that interact with one another during the developmental process create biological and, thus, phenotypical diversities. Mutations is genetic information that are expressed among organisms via gene expression, which is the translation of genetic information into a phenotypic character. Evolution is the change in a heritable trait in a population across generations since mutations generate variations in the heritable traits; they are considered the raw material for evolution. Therefore, beneficial mutation accumulations during the developmental processes could generate more phenotypic variations, which increases their gene frequency and affect the capacity of phenotypic evolution.

Somatic cells

The somatic mutation theory of ageing states that accumulation of mutations in somatic cells is the primary cause of aging. A comparison of somatic mutation rate across several mammal species found that the total number of accumulated mutations at the end of lifespan was roughly equal across a broad range of lifespans. The authors state that this strong relationship between somatic mutation rate and lifespan across different mammalian species suggests that evolution may constrain somatic mutation rates, perhaps by selection acting on different DNA repair pathways.

Antagonistic pleiotropy

Medawar's theory was critiqued and later further developed by George C. Williams in 1957. Williams noted that senescence may be causing many deaths even if animals are not 'dying of old age.' He began his hypothesis with the idea that ageing can cause earlier senescence due to the competitive nature of life. Even a small amount of ageing can be fatal; hence natural selection does indeed care and ageing is not cost-free.

Williams eventually proposed his own hypothesis called antagonistic pleiotropy. Pleiotropy, alone, means one mutation that cause multiple effects on phenotype. Antagonistic pleiotropy on the other hand deals with one gene that creates two traits with one being beneficial and the other detrimental. In essence, this refers to genes that offer benefits early in life, but later accumulate a cost. In other words, antagonistic pleiotropy is when the resultant relationship between two traits is negative. It's when one phenotypic trait positively affects current reproduction at the expense of later accelerated senescence, growth, and maintenance. Antagonistic pleiotropy is permanent unless a mutation that modifies the effects of the primary locus occurs.

Although antagonistic pleiotropy is a prevailing theory today, this is largely by default, and has not been well verified. Research has shown that this is not true for all genes and may be thought of as partial validation of the theory, but it cuts the core premise: that genetic trade-offs are the root cause of ageing.

In breeding experiments, Michael R. Rose selected fruit flies for long lifespan. Based on antagonistic pleiotropy, Rose expected that this would surely reduce their fertility. His team found that they were able to breed flies that lived more than twice as long as the flies they started with, but to their surprise, the long-lived, inbred flies actually laid more eggs than the short-lived flies. This was another setback for pleiotropy theory, though Rose maintains it may be an experimental artifact.

Disposable soma theory

A third mainstream theory, proposed in 1977 by Thomas Kirkwood, presumes that the body must budget the resources available to it. The body uses resources derived from the environment for metabolism, for reproduction, and for repair and maintenance, and the body must compromise when there is a finite supply of resources. The theory states that this compromise causes the body to reallocate energy to the repair function that causes the body to gradually deteriorate with age.

A caveat to this theory suggests that this reallocation of energy is based on time instead of limiting resources. This concept focuses on the evolutionary pressure to reproduce in a set, optimal time period that is dictated by age and ecological niche. The way that this is successful is through the allocation of time and energy in damage repair at the cellular level resulting in an accumulation of damage and a decreased lifespan relative to organisms with longer gestation. This concept stems from a comparative analysis of genomic stability in mammalian cells.

One opposing argument is based on the effect of caloric restriction, which lengthens life.However, dietary restriction has not been shown to increase lifetime reproductive success (fitness), because when food availability is lower, reproductive output is also lower. Moreover, calories are not the only resource of possibly limited supply to an organism that could have an effect on multiple dimensions of fitness.

DNA damage/error theory

Just like DNA mutation and expression have phenotypic effects on organisms, DNA damage and mutation accumulation also have phenotypic consequences in older humans. Damage to macromolecules such as DNA, RNA, and proteins along with the deterioration of tissues and organs are the basis of aging. Species-specific rates of aging are due to deleterious changes which manifest after the reproductive phase. "Mitochondrial DNA (mtDNA) regulates cellular metabolism, apoptosis and oxidative stress control". Damage to mtDNA is therefore another contributing factor to phenotypes related to aging. Neurodegeneration and cancer are two factors that manifest with DNA damage; therefore, we need to understand the change in the association between DNA damage and DNA repair as we age in order to be aware of age-related diseases and develop lifestyles that could possibly promote a healthy life span.

The DNA damage theory of aging postulates that DNA damage is ubiquitous in the biological world and is the primary cause of ageing. The theory is based on the idea that ageing occurs over time due to the damage of the DNA. As an example, studies of mammalian brain and muscle have shown that DNA repair capability is relatively high during early development when cells are dividing mitotically, but declines substantially as cells enter the post-mitotic state.

The effect of reducing expression of DNA repair capability is increased accumulation of DNA damage. This impairs gene transcription and causes the progressive loss of cellular and tissue functions that define aging. As a response to DNA damage, one of the responses triggered by oxidative stress is the activation of the p53. The p53 protein binds to DNA, then stimulates the production of a p21, which is also known as cyclin-dependent kinase inhibitor 1. This ensures that the cell cannot enter the next stage of cell division unless the DNA damage is repaired. However, the p21 cells can trigger apoptosis. Apoptosis or programmed cell death is associated with gradual degradation of the immune system, skeletal muscle, and aging-associated malfunction.

Naked Mole Rat. Picture taken by: Ltshears - Trisha M Shears.

Telomere theory of ageing

Telomeres are recurring nucleotide sequences that protect the ends of our chromosome; they are sensitive to oxidative stress and degrade during chromosomal replication. Telomerase is a ribonucleotide protein that helps repair and replace degraded telomeres. However, telomerase is not universally expressed in all cells. In humans and other large mammals, telomerase expression is progressively shut off after early embryo development, remaining active only in germline cells. As such, human telomeres shorten with each cellular replication. When telomeres reach a certain length, cell division arrests to prevent DNA damage. This is called cellular senescence. New research has also shown that there is an association between telomere shortening and mitochondrial dysfunction. Nevertheless, over-expression of telomerase increases the chances of cancer. If telomeres stay in repair, there is a greater chance of longevity, but there is also more cell division and a greater chance of mutation, which could result in cancer. Therefore, a long-lived cell is just a time bomb. Enhancing telomerase activity is, therefore, not a solution; it only allows the cells to live longer. Naked mole rats have high telomerase activity, they live long, and were thought by some to never get cancer; and therefore possibly be an exception to this hypothesis. Naked mole rats do get cancer, however.

Programmed maintenance theories

Theories, such as Weismann's "programmed death" theory, suggest that deterioration and death due to ageing are a purposeful result of an organism's evolved design, and are referred to as theories of programmed ageing or adaptive ageing.

The programmed maintenance theory based on evolvability suggests that the repair mechanisms are controlled by a common control mechanism capable of sensing conditions, such as caloric restriction, and may be responsible for lifespan in particular species. In this theory, the survival techniques are based on control mechanisms instead of individual maintenance mechanism, which you see in the non-programmed theory of mammal ageing.

A non-programmed theory of mammal ageing states that different species possess different capabilities for maintenance and repair. Longer-lived species possess many mechanisms for offsetting damage due to causes such as oxidation, telomere shortening, and other deteriorative processes. Shorter-lived species, having earlier ages of sexual maturity, have less need for longevity and thus did not evolve or retain the more-effective repair mechanisms. Damage therefore accumulates more rapidly, resulting in earlier manifestations and shorter lifespan. Since there are a wide variety of ageing manifestations that appear to have very different causes, it is likely that there are many different maintenance and repair functions.

Selective shadow

Selective shadowing is one of the evolutionary theories of aging based on the presumption that selection of an individual generally decreases once they essentially pass the sexual mature phase. As a result, this forms a shadow without the account of sexual fitness, which is no longer considered as an individual ages. This supports the idea that the force of natural selection declines as a function of age, which was first introduced by Peter B. Medewar and J.B.S Haldane.

"The key conceptual insight that allowed Medawar, Williams, and others, to develop the evolutionary theory of aging is based on the notion that the force of natural selection, a measure of how effectively selection acts on survival rate or fecundity as a function of age, declines with progressive age."

Medewar developed a model that highlights this, showing the decrease in the survival rate of a population as an individual ages, however the reproduction rate stays constant. The reproduction probability typically peaks during sexual maturity and decreases as an individual ages, while the rest of the population decreases with age as they enter the selection shadow. The model also supports Medewars' theory that due to dangerous and unpredicted conditions in the environment such as diseases, climate changes and predators, many individuals die not too long after sexual maturation. Consequently, the probability of an individual surviving and suffering from age related effects is relatively low.

In the same way, many beneficial mutations are selected against if they have a positive effect on an individual later on in life. For instance if a beneficial or deleterious mutation occurs only after an individual's reproductive phase, then it will not affect fitness, which therefore can not be selected against. Subsequently, these later mutations and effects are considered to be in the "shadow region" of selection."

Natural selection

Group selection

Group selection is based on the idea that all members of a given group will either succeed or fail together depending on the circumstance. With this mechanism, genetic drift occurs collectively to all in the group and sets them apart from other groups of its own species. This is different than individual selection, as it focuses on the group rather than the individual.

Often also postreproductive individuals make intergenerational transfers: bottlenose dolphins and pilot whales guard their grandchildren; there is cooperative breeding in some mammals, many insects and about 200 species of birds; sex differences in the survival of anthropoid primates tend to correlate with the care to offspring; or an Efe infant is often attended by more than 10 people. Lee developed a formal theory integrating selection due to transfers (at all ages) with selection due to fertility.

Evolvability

Evolvability is the concept that a species should profit from faster genetic adaptation to its present environment. In the following examples, this is used to argue that eliminating old individuals might benefit the species overall.

Skulachev (1997) has suggested that programmed ageing assists the evolution process by providing a gradually increasing challenge or obstacle to survival and reproduction, and therefore enhancing the selection of beneficial characteristics.

Goldsmith (2008) proposed that though increasing the generation rate and evolution rate is beneficial for a species, it is also important to limit lifespan so older individuals will not dominate the gene pool.

Yang (2013)'s model is also based on the idea that ageing accelerates the accumulation of novel adaptive genes in local populations. However, Yang changed the terminology of "evolvability" into "genetic creativity" throughout his paper to facilitate the understanding of how ageing can have a shorter-term benefit than the word "evolvability" would imply.

Lenart and Vašku (2016) have also invoked evolvability as the main mechanism driving evolution of ageing. However, they proposed that even though the actual rate of aging can be an adaptation the aging itself is inevitable. In other words, evolution can change the speed of aging but some ageing no matter how slow will always occur.

Mortality

Constant failure rate over time

Mortality is the number of deaths, in a particular group, over a specific time period. There are two types of mortality: intrinsic and extrinsic mortality. Intrinsic mortality is defined as mortality due to ageing, the physiological decline due to innate processes, whereas extrinsic mortality is the result of environmental factors such as for example predation, starvation, accidents and others. Flying animals such as bats, for example, have fewer predators, and therefore have a low extrinsic mortality. Birds are warm-blooded and similar in size to many small mammals, yet often live 5–10 times as long. They face less predation than ground-dwelling mammals, and thus have lower extrinsic mortality.

When examining the body-size vs. lifespan relationship, one also observes that predatory mammals tend to live longer than prey mammals in a controlled environment, such as a zoo or nature reserve. The explanation for the long lifespans of primates (such as humans, monkeys, and apes) relative to body size is that they manage to achieve lower extrinsic mortality due to their intelligence.

Potential immortality of the germ line

Individual organisms are ordinarily mortal; they age and die, while the germlines which connect successive generations are potentially immortal. The basis for this difference is a fundamental problem in biology. The Russian biologist and historian Zhores A. Medvedev considered that the accuracy of genome replicative and other synthetic systems alone cannot explain the immortality of germ lines. Rather Medvedev thought that known features of the biochemistry and genetics of sexual reproduction indicate the presence of unique information maintenance and restoration processes at the different stages of gametogenesis. In particular, Medvedev considered that the most important opportunities for information maintenance of germ cells are created by recombination during meiosis and DNA repair; he saw these as processes within the germ cells that were capable of restoring the integrity of DNA and chromosomes from the types of damage that cause irreversible ageing in somatic cells.

Diseases

Progeroid syndromes

Progeroid syndromes are genetic diseases that are linked to premature aging. Progeroid syndromes are characterized by having features that resemble those of physiological aging such as hair loss and cardiovascular disease.

Progeria

Progeria is a single-gene genetic disease that cause acceleration of many or most symptoms of ageing during childhood. It affects about 1 in 4-8 million births. Those who have this disease are known for failure to thrive and have a series of symptoms that cause abnormalities in the joints, hair, skin, eyes, and face. Most who have the disease only live to about age 13. Although the term progeria applies strictly speaking to all diseases characterized by premature aging symptoms, and is often used as such, it is often applied specifically in reference to Hutchinson–Gilford progeria syndrome (HGPS). Children diagnosed with HGPS develop prominent facial features such as a small face, thin lips, small chin, and protruding ears. Although progeria can cause physical abnormalities on a child, it does not impact their motor skills or intellectual advancement. Those who have HGPS are prone to suffer from neurological and cardiovascular disorders. HGPS is caused by a point mutation in the gene that encodes lamin A protein. Lamin A promotes genetic stability by maintaining levels of proteins that have key roles in non-homologous end joining and homologous recombination. Mouse cells deficient for maturation of prelamin A show increased DNA damage and chromosome aberrations and have increased sensitivity to DNA damaging agents. In HGPS, the inability to adequately repair DNA damages due to defective A-type lamin may cause aspects of laminopathy-based premature aging.

Werner Syndrome

Werner syndrome, also known as "adult progeria", is another single-gene genetic disease. it is caused by a mutation in the wrn gene. It affects about 1 in 200,000 people in the United States. This syndrome starts to affect individuals during the teenage years, preventing teens from growing at puberty. There are four common traits of Werner's syndrome: cataracts in both eyes, changes in skin similar to scleroderma, short stature, and early graying and loss of hair. Once the individual reaches the twenties, there is generally a change in hair color, skin, and voice. The average life expectancy of someone with this disease is around 46 years. This condition can also affect the weight distribution between the arms, legs, and torso. Those who have Werner syndrome are at an increased risk for cataracts, type 2 diabetes, different types of cancers, and atherosclerosis. The finding that WRN protein interacts with DNA-PKcs and the Ku protein complex, combined with evidence that WRN deficient cells produce extensive deletions at sites of joining of non-homologous DNA ends, suggests a role for WRN protein in the DNA repair process of non-homologous end joining. WRN protein also appears to play a role in resolving recombination intermediate structures during homologous recombinational repair of DNA double-strand breaks.

Other progeroid syndromes

Bloom syndrome is a rare autosomal recessive disorder that is characterized by short stature, chromosomal instability, predisposition to cancer, and sun-sensitive skin. Those with Bloom syndrome can also have learning disabilities and have an increased risk of developing chronic obstructive pulmonary disease (COPD) and disease.

Cockayne syndrome is a homozygous or heterozygous mutation that results in short stature, abnormalities in head size, and slow growth and development.

Rothmund–Thomson syndrome is a rare autosomal recessive disorder that affects the skin. It is characterized by the sparse hair, juvenile cataracts, skeletal abnormalities, and stunted growth.

Biogerontology

Theories of ageing affect efforts to understand and find treatments for age-related conditions:

  • Those who believe in the idea that ageing is an unavoidable side effect of some necessary function (antagonistic pleiotropy or disposable soma theories) logically tend to believe that attempts to delay ageing would result in unacceptable side effects to the necessary functions. Altering ageing is therefore "impossible", and study of ageing mechanisms is of only academic interest.
  • Those believing in default theories of multiple maintenance mechanisms tend to believe that ways might be found to enhance the operation of some of those mechanisms. Perhaps they can be assisted by antioxidants or other agents.
  • Those who believe in programmed ageing suppose that ways might be found to interfere with the operation of the part of the ageing mechanism that appears to be common to multiple symptoms, essentially "slowing down the clock" and delaying multiple manifestations. Such effect might be obtained by fooling a sense function. One such effort is an attempt to find a "mimetic" that would "mime" the anti-ageing effect of calorie restriction without having to actually radically restrict diet.

Senescence

From Wikipedia, the free encyclopedia https://en.wikipedia.org/wiki/Senescenc...