Disposable soma theory of aging

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In biogerontology, the disposable soma theory of aging states that organisms age due to an evolutionary trade-off between growth, reproduction, and DNA repair maintenance. [1] Formulated by British biologist Thomas Kirkwood, the disposable soma theory explains that an organism only has a limited amount of resources that it can allocate to its various cellular processes. [2] Therefore, a greater investment in growth and reproduction would result in reduced investment in DNA repair maintenance, leading to increased cellular damage, shortened telomeres, accumulation of mutations, compromised stem cells, and ultimately, senescence. Although many models, both animal and human, have appeared to support this theory, parts of it are still controversial. Specifically, while the evolutionary trade-off between growth and aging has been well established, the relationship between reproduction and aging is still without scientific consensus, and the cellular mechanisms largely undiscovered. [3]

Contents

Background and history

British biologist Thomas Kirkwood first proposed the disposable soma theory of aging in a 1977 Nature review article. [1] The theory was inspired by Leslie Orgel's Error Catastrophe Theory of Aging, which was published fourteen years earlier, in 1963. Orgel believed that the process of aging arose due to mutations acquired during the replication process, and Kirkwood developed the disposable soma theory in order to mediate Orgel's work with evolutionary genetics. [1]

Principles

The disposable soma theory of aging posits that there is a trade-off in resource allocation between somatic maintenance and reproductive investment. Too low an investment in self-repair would be evolutionarily unsound, as the organism would likely die before reproductive age. However, too high an investment in self-repair would also be evolutionarily unsound due to the fact that one's offspring would likely die before reproductive age. Therefore, there is a compromise and resources are partitioned accordingly. However, this compromise is thought to damage somatic repair systems, which can lead to progressive cellular damage and senescence. [4] Repair costs can be categorized into three groups: (1) the costs of increased durability of nonrenewable parts; (2) the costs of maintenance involving cell renewal, and (3) the costs of intracellular maintenance. [5] In a nutshell, aging and decline is essentially a trade-off for increased reproductive robustness in youth.[ citation needed ]

Mechanisms

The IGF-1 pathway, which represses FOXO, thus preventing gene expression of longevity-inducing proteins IGF-1Pathway.png
The IGF-1 pathway, which represses FOXO, thus preventing gene expression of longevity-inducing proteins

Growth and somatic maintenance

Much research has been done on the antagonistic effects of increased growth on lifespan. Specifically, the hormone insulin-like growth factor 1 (IGF-1), binds to a cell receptor, leading to a phosphorylation cascade. This cascade results in kinases phosphorylating forkhead transcription factor (FOXO), deactivating it. Deactivation of FOXO results in an inability to express genes involved in responding to oxidative stress response, such as antioxidants, chaperones, and heat-shock proteins. [6] Additionally, uptake of IGF-1 stimulates the mTOR pathway, which activates protein synthesis (and therefore growth) through upregulation of the translation-promoting S6K1, and also inhibits autophagy, a process necessary for recycling of damaged cellular products. [7] Decline of autophagy causes neurodegeneration, protein aggregation and premature aging. [8] Lastly, studies have also indicated that the mTOR pathway also alters immune responses and stimulates cyclin-dependent kinase (CDK) inhibitors such as p16 and p21. This leads to alteration of the stem-cell niche and results in stem cell exhaustion, another theorized mechanism of aging. [9]

Reproduction and somatic maintenance

While reproduction inhibits lifespan with regard to multicellular organisms, the precise mechanism responsible for this effect remains unclear. Although many models do illustrate an inverse relationship, and the theory makes sense from an evolutionary perspective, the cellular mechanisms have yet to be explored. However, with regards to cellular replication, the progressive shortening of telomeres is a mechanism which limits the amount of generations of a single cell may undergo. [10] Furthermore, in unicellular organisms like Saccharomyces cerevisiae , the formation of extrachromosomal rDNA circles (ERCs) in mother cells (but not daughter cells) upon every subsequent division is an identifiable type of DNA damage that is associated with replication. These ERCs accumulate over time and eventually trigger replicative senescence and death of the mother cell. [11]

Evidence

Growth and aging

There is a large body of evidence indicating the negative effects of growth on longevity across many species. As a general rule, individuals of a smaller size generally live longer than larger individuals of the same species.[ citation needed ]

Animal models

In dwarf models of mice, such Snell or Ames mice, mutations have arisen, either rendering them incapable of producing IGF-1 or unable to have adequate receptors for IGF-1 uptake. Furthermore, mice injected with growth hormone have been shown to have progressive weight loss, roughing of the coat, curvature of the spine, enlargement of the organs, kidney lesions and increased cancer risk. [12] This effect is also seen in different breeds of dogs, where smaller breeds of dogs typically live significantly longer compared to their larger counterparts. Selectively bred for their small size, smaller dog breeds like the Chihuahua (average lifespan of 15–20 years) have the B/B genotype for the IGF-1 haplotype, reducing the amount of IGF-1 produced. Conversely, large dogs like the Great Dane (average lifespan of 6–8 years) are homozygous for the IGF-1 I allele, which increases the amount of IGF-1 production. [13]

Human models

Initially, it was believed that growth hormone actually prolonged lifespan due to a 1990 study that indicated that injection of growth hormone to men over 60 years of age appeared to reverse various biomarkers implicated in aging, such as decreased muscle mass, bone density, skin thickness, and increased adipose tissue. [14] However, a 1999 study found that administering growth hormone also significantly increased mortality rate. [15] Recent genomic studies have confirmed that the genes involved in growth hormone uptake and signaling are largely conserved across a plethora of species, such as yeast, nematodes, fruit flies, mice and humans. [16] These studies have also shown that individuals with Laron syndrome, an autosomal recessive disorder resulting in dwarfism due to defects in growth hormone receptors, have increased lifespan. Additionally, these individuals have much lower incidences of age-related diseases such as type 2 diabetes and cancer. [17] Lastly, human centenarians around the world are disproportionately of short stature, and have low levels of IGF-1. [18]

Reproduction and aging

Numerous studies have found that lifespan is inversely correlated with both the total amount of offspring birthed, as well as the age at which females first gives birth, also known as primiparity. [19] Additionally, it has been found that reproduction is a costly mechanism that alters the metabolism of fat. Lipids invested in reproduction would be unable to be allocated to support mechanisms involved in somatic maintenance. [20]

Animal models

The disposable soma theory has been consistent with the majority of animal models. It was found in numerous animal studies that castration or genetic deformities of reproduction organs was correlated with increased lifespan. [21] [22] [23] Moreover, in red squirrels, it was found that females with an early primiparity achieved the highest immediate and lifetime reproductive success. However, it was also found that these same individuals had a decreased median and maximum lifespan. Specifically squirrels who mated earlier had a 22.4% rate of mortality until two years of age compared to a 16.5% rate of mortality in late breeders. In addition, these squirrels had an average maximum lifespan of 1035 days compared to an average maximum lifespan of 1245 days for squirrels that bred later. [19]

In another study, researchers selectively bred fruit flies over three years to develop two different strains, an early-reproducing strain and a late-reproducing strain. The late-reproducing line had a significantly longer lifespan than the early-reproducing line. Even more telling was that when the researchers introduced a mutation in the ovarian-associated gene ovoD1, resulting in defective oogenesis, the differences in lifespan between the two lines disappeared. The researchers in this case concluded that "aging has evolved primarily because of the damaging effects of reproduction earlier in life". [24]

Prominent aging researcher Steven Austad also performed a large-scale ecological study on the coast of Georgia in 1993. Austad isolated two opossum populations, one from the predator-infested mainland and one from the predator-absent nearby island of Sapelo. According to the disposable soma theory, a genetically isolated population subject to low environmentally-induced mortality would evolve delayed reproduction and aging. This is because without the pressure of predation, it would be evolutionarily advantageous to allocate more resources to somatic maintenance than reproduction, as early offspring mortality would be low. As predicted, even after controlling for predation, the isolated population had a longer lifespan, delayed primiparity, and reduced aging biomarkers such as tail collagen cross-linking. [25]

Human models

In general, only a few studies exist in human models. It was found that castrated men live longer than their fertile counterparts. [26] Further studies found that in British women, primiparity was earliest in women who died early and latest in women who died at the oldest ages. Furthermore, increased number of children birthed was associated with a decreased lifespan. [27] A final study found that female centenarians were more likely to have children in later life compared to the average, especially past the age of 40. The researchers discovered that 19.2% of female centenarians had their first child after the age of 40, compared to 5.5% of the rest of the female population. [28]

Relationship between cell damage and aging

The naked mole rat has a disproportionately long life of 30 years through efficient cellular repair mechanisms. Naked Mole Rat Eating.jpg
The naked mole rat has a disproportionately long life of 30 years through efficient cellular repair mechanisms.

There are numerous studies that support cellular damage, often due to a lack of somatic maintenance mechanisms, as a primary determinant for aging, and these studies have given rise to the free radical theory of aging and the DNA damage theory of aging. One study found that the cells of short-living rodents in vitro show much greater mutation rates and a general lack of genome surveillance compared to human cells and are far more susceptible to oxidative stress. [29] Other studies have been conducted on the naked mole rat, a rodent species with remarkable longevity (30 years), capable of outliving the brown rat (3 years) by ten-fold. Additionally, almost no incidence of cancer has ever been detected in naked mole rats. Nearly all of the differences found between these two organisms, which are otherwise rather genetically similar, was in somatic maintenance. Naked mole rats were found to have higher levels of superoxide dismutase, a reactive oxygen species clearing antioxidant. In addition, naked mole rats had higher levels of base excision repair, DNA damage response signaling, homologous recombination repair, mismatch repair, nucleotide excision repair, and non-homologous end joining. In fact, many of these processes were near or exceeded human levels. Proteins from naked mole rats were also more resistant to oxidation, misfolding, ubiquitination, and had increased translational fidelity. [30]

Further studies have been conducted on patients with Hutchinson-Gilford Progeria Syndrome (HGPS), a condition that leads to premature aging. Patients with HGPS typically age about seven times faster than average and usually succumb to the disease in their early teens. Patients with HGPS have cellular defects, specifically in the lamin proteins, which regulate the organization of the lamina and nuclear envelope for mitosis. [31] A-type lamins promote genetic stability by maintaining levels of proteins that have key roles in the repair processes of non-homologous end joining and homologous recombination. [32] Mouse cells deficient for maturation of prelamin A show increased DNA damage and chromosome aberrations and have increased sensitivity to DNA damaging agents. [33]

Lastly, as mentioned previously, it has been found that the suppression of autophagy is associated with reduced lifespan, while stimulation is associated with extended lifespan. Activated in times of caloric restriction, autophagy is a process that prevents cellular damage through clearance and recycling of damaged proteins and organelles. [34]

Criticism

One of the main weaknesses of the disposable soma theory is that it does not postulate any specific cellular mechanisms to which an organism shifts energy to somatic repair over reproduction. Instead, it only offers an evolutionary perspective on why aging may occur due to reproduction. Therefore, parts of it are rather limited outside of the field of evolutionary biology. [3]

Caloric restriction

Schematic showing the reallocation of energy investment towards self-repair during caloric restriction Soma Disposable.png
Schematic showing the reallocation of energy investment towards self-repair during caloric restriction

Critics have pointed out the supposed inconsistencies of the disposable soma theory due to the observed effects of caloric restriction, which is correlated with increased lifespan. [35] Although it activates autophagy, according to classical disposable soma principles, with less caloric intake, there would less total energy to be distributed towards somatic maintenance, and decreased lifespan would be observed (or at least the positive autophagic effects would be balanced out). However, Kirkwood, alongside his collaborator Darryl P. Shanley, assert that caloric restriction triggers an adaptive mechanism which causes the organism to shift a higher proportion of resources to somatic maintenance, away from reproduction. [36] This theory is supported by multiple studies, which show that caloric restriction typically results in impaired fertility, but leave an otherwise healthy organism. [37] [38] Evolutionarily, an organism would want to delay reproduction to when resources were more plentiful. During a resource-barren period, it would evolutionarily unwise to invest resources in progeny that would be unlikely to survive in famine. Mechanistically, the NAD-dependent deacetylase Sirtuin 1 (SIRT-1) is upregulated during low-nutrient periods. SIRT-1 increases insulin sensitivity, decreases the amount of inflammatory cytokines, stimulates autophagy, and activates FOXO, the aforementioned protein involved in activating stress response genes. SIRT-1 is also found to result in decreased fertility. [39]

In additional to differential partitioning of energy allocation during caloric restriction, less caloric intake would result in less metabolic waste in the forms of free radicals like hydrogen peroxide, superoxide and hydroxyl radicals, which damage important cellular components, particularly mitochondria. Elevated levels of free radicals in mice has been correlated with neurodegeneration, myocardial injury, severe anemia, and premature death. [40]

No changes were observed in the spontaneous chromosomal mutation frequency of dietary restricted mice (aged 6 and 12 months) compared to ad libitum fed control mice. [41] Thus dietary restriction appears to have no appreciable effect on spontaneous mutation in chromosomal DNA, and the increased longevity of dietary restricted mice apparently is not attributable to reduced chromosomal mutation frequency.[ citation needed ]

The grandmother hypothesis

Another primary criticism of the disposable soma theory is that it fails to account for why women tend to live longer than their male counterparts. [42] After all, females invest significantly more resources into reproduction and according to the classical disposable soma principles, this would compromise energy diverted to somatic maintenance. However, this can be reconciled with the grandmother hypothesis. The Grandmother Hypothesis states that menopause comes about into older women in order to restrict the time of reproduction as a protective mechanism. This would allow women to live longer and increase the amount of care they could provide to their grandchildren, increasing their evolutionary fitness. [43] And so, although women do invest a greater proportion of resources into reproduction during their fertile years, their overall reproductive period is significantly shorter than men, who are able of reproduction during and even beyond middle age. [44] Additionally, males invest more resources into growth compare to females, which is correlated with decreased lifespan. Other variables such as increased testosterone levels in males are not accounted for. Increased testosterone is often associated with reckless behaviour, which may lead to a high accidental death rate. [45]

Contradicting models

A few contradicting animal models weaken the validity of the disposable soma theory. This includes studies done on the aforementioned naked mole rats. In these studies, it was found that reproductive naked mole rats actually show significantly increased lifespans compared to non-reproductive individuals, which contradicts the principles of disposable soma. However, although these naked mole rats are mammalian, they are highly atypical in terms of aging studies and may not serve as the best model for humans. For example, naked mole rats have a disproportionately high longevity quotient and live in eusocial societies, where breeding is usually designated to a queen. [46]

Sex biases and environment

The disposable soma theory is tested disproportionately on female organisms for the relationship between reproduction and aging, as females carry a greater burden in reproduction. [47] Additionally, for the relationship between growth and aging, studies are disproportionately conducted on males, to minimize the hormonal fluctuations that occur with menstrual cycling. [48] Lastly, genetic and environmental factors, rather than reproductive patterns, may explain the variations in human lifespan. For example, studies have shown that poorer individuals, to whom nutritious food and medical care is less accessible, typically have higher birth rates and earlier primiparity. [49]

Related Research Articles

Senescence 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 resulting 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.

<span class="mw-page-title-main">Life extension</span> Concept of extending human lifespan by improvements in medicine or biotechnology

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", postulate that future breakthroughs in tissue rejuvenation, stem cells, regenerative medicine, molecular repair, gene therapy, pharmaceuticals, and organ replacement 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.

In cellular biology, a somatic cell, or vegetal cell, is any biological cell forming the body of a multicellular organism other than a gamete, germ cell, gametocyte or undifferentiated stem cell. Somatic cells compose the body of an organism and divide through mitosis.

<span class="mw-page-title-main">Naked mole-rat</span> Burrowing eusocial rodent

The naked mole-rat, also known as the sand puppy, is a burrowing rodent native to the Horn of Africa and parts of Kenya, notably in Somali regions. It is closely related to the blesmols and is the only species in the genus Heterocephalus.

<span class="mw-page-title-main">Insulin-like growth factor 1</span> Protein found in humans

Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a hormone similar in molecular structure to insulin which plays an important role in childhood growth, and has anabolic effects in adults. In the 1950s IGF-1 was called "sulfation factor" because it stimulated sulfation of cartilage in vitro, and in the 1970s due to its effects it was termed "nonsuppressible insulin-like activity" (NSILA).

The DAF-2 gene encodes for the insulin-like growth factor 1 (IGF-1) receptor in the worm Caenorhabditis elegans. DAF-2 is part of the first metabolic pathway discovered to regulate the rate of aging. DAF-2 is also known to regulate reproductive development, resistance to oxidative stress, thermotolerance, resistance to hypoxia, and resistance to bacterial pathogens. Mutations in DAF-2 and also Age-1 have been shown by Cynthia Kenyon to double the lifespan of the worms. In a 2007 episode of WNYC’s Radiolab, Kenyon called DAF-2 "the grim reaper gene.”

<span class="mw-page-title-main">Spermidine</span> Chemical compound

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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 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.

Following is a list of topics related to life extension:

The following outline is provided as an overview of and topical guide to life extension:

Ageing is the process of becoming older. The term refers mainly to humans, many other animals, and fungi, whereas for example, bacteria, perennial plants and some simple animals are potentially biologically immortal. In a broader sense, ageing can refer to single cells within an organism which have ceased dividing, or to the population of a species.

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 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.

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.

David Gems is a British geneticist who studies the biology and genetics of ageing (biogerontology). He is Professor of Biogerontology at the Research Department of Genetics, Evolution and Environment, University College London and he is a co-founder and Research Director of the UCL Institute of Healthy Ageing. His work concerns understanding the underlying causes of aging. His research laboratory tests theories of aging and develops new ones using a short-lived animal model C. elegans.

The reproductive-cell cycle theory posits that the hormones that regulate reproduction act in an antagonistic pleiotrophic manner to control aging via cell cycle signaling; promoting growth and development early in life in order to achieve reproduction, but later in life, in a futile attempt to maintain reproduction, become dysregulated and drive senescence. Rather than seeing aging as a loss of functionality as we get older, this theory defines aging as any change in an organism over time, as evidenced by the fact that if all chemical reactions in the body were stopped, no change, and thus no aging, would occur. Since the most important change in an organism through time is the chemical reactions that result in a single cell developing into a multicellular organism, whatever controls these chemical reactions that regulate cell growth, development, and death, is believed to control aging. The theory argues that these cellular changes are directed by reproductive hormones of the hypothalamic-pituitary-gonadal axis. Receptors for reproductive hormones have been found to be present in all tissues of the body. Thus, HPG axis hormones normally promote growth and development of the organism early in life in order to achieve reproduction. Hormones levels then begin to change in men around age 30 and more abruptly in women when they reach menopause, around age 50. When the HPG axis becomes unbalanced, cellular growth and development is dysregulated, and cell death and dysfunction can occur, both of which can initiate senescence, the accumulated damage to cells, tissues, and organs that occurs with the passage of time and that is associated with functional loss during aging.

<span class="mw-page-title-main">Genetics of aging</span> Overview of the genetics of aging

Genetics of aging is generally concerned with life extension associated with genetic alterations, rather than with accelerated aging diseases leading to reduction in lifespan.

Extrinsic mortality is the sum of the effects of external factors, such as predation, starvation and other environmental factors not under control of the individual that cause death. This is opposed to intrinsic mortality, which is the sum of the effects of internal factors contributing to normal, chronologic aging, such as, for example, mutations due to DNA replication errors, and which determined species maximum lifespan. Extrinsic mortality plays a significant role in evolutionary theories of aging, as well as the discussion of health barriers across socioeconomic borders.

In life history theory, the cost of reproduction hypothesis is the idea that reproduction is costly in terms of future survival and reproduction. This is mediated by various mechanisms, with the two most prominent being hormonal regulation and differential allocation of internal resources.

A somatic mutation is a change in the DNA sequence of a somatic cell of a multicellular organism with dedicated reproductive cells; that is, any mutation that occurs in a cell other than a gamete, germ cell, or gametocyte. Unlike germline mutations, which can be passed on to the descendants of an organism, somatic mutations are not usually transmitted to descendants. This distinction is blurred in plants, which lack a dedicated germline, and in those animals that can reproduce asexually through mechanisms such as budding, as in members of the cnidarian genus Hydra.

Germ-Soma Differentiation is the process by which organisms develop distinct germline and somatic cells. The development of cell differentiation has been one of the critical aspects of the evolution of multicellularity and sexual reproduction in organisms. Multicellularity has evolved upwards of 25 times, and due to this there is great possibility that multiple factors have shaped the differentiation of cells. There are three general types of cells: germ cells, somatic cells, and stem cells. Germ cells lead to the production of gametes, while somatic cells perform all other functions within the body. Within the broad category of somatic cells, there is further specialization as cells become specified to certain tissues and functions. In addition, stem cell are undifferentiated cells which can develop into a specialized cell and are the earliest type of cell in a cell lineage. Due to the differentiation in function, somatic cells are found only in multicellular organisms, as in unicellular ones the purposes of somatic and germ cells are consolidated in one cell.

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Calorie restriction

Biology of aging