The disposable soma theory of aging states that organisms age due to an evolutionary trade-off between growth, reproduction, and DNA repair maintenance. Formulated by Thomas Kirkwood,
the disposable soma theory explains that an organism only has a limited
amount of resources or "soma" that it can allocate to its various cellular processes.
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.
Background and history
British biologist Thomas Kirkwood first proposed the disposable soma theory of aging in a 1977 Nature review article. 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.
Principles
The disposable soma theory of aging acts on the premise that there is a tradeoff 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. 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. In a nutshell, aging and decline is essentially a tradeoff for increased reproductive robustness in youth.
Mechanisms
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.
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. Decline of autophagy causes neurodegeneration, protein aggregation and premature aging. 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.
Reproduction and somatic maintenance
The
mechanism of why reproduction inhibits lifespan with regards to
multicellular organisms is still 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. 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.
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.
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. 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.
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. However, a 1999 study found that administering growth hormone also significantly increased mortality rate. 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. 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. Lastly, human centenarians around the world are disproportionately of short stature, and have low levels of IGF-1.
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. 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.
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. 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.
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".
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.
Human models
In general, only a few studies exist in human models. It was found that castrated men live longer than their fertile counterparts.
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.
A final study found that female centenarians were more likely to have
children in later life compared 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.
Relationship between cell damage and aging
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.
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 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.
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.
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.
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.
Caloric restriction
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. 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. This theory is supported by multiple studies, which show that caloric restriction typically results in impaired fertility, but leave an otherwise healthy organism.
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.
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.
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.
Afterall, 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. 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.
Additionally, males invest more resources into growth, and have
significantly higher levels of IGF-1 compared 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 behavior, which may lead to a high accidental
death rate.
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.
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.
Additionally, for the relationship between growth and aging, studies
are disproportionately conducted on males, to minimize the hormonal fluctuations that occur with menstrual cycling. 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.
