Evolution of ageing

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.

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 indeed 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."