Recent advances in the evolution of aging and lifespan

Evolutionary trade-offs may explain the significant variation in lifespan, researchers say in new review.

Aging is a common phenomenon among organisms, however, lifespan tends to vary across different species to a significant extent among vertebrates themselves. Aging occurs due to the gradual increase in DNA damage, disruption of cellular organelles, deregulation of protein function, disrupted metabolism and oxidative stress [1].

Longevity.Technology: The differences in lifespan are driven by trade-offs and evolutionary trajectories in the genomes of organisms. Age-specific selection also impacts allele (variations of a gene) frequencies in a population. This in turn impacts environment-specific mortality risk and disease susceptibility. Moreover, mutational processes are influenced by life history and age in both somatic and germline cells.

Now, a new review published in Trends in Genetics discusses recent advances in the evolution of aging at population, organismal and cellular scales.

The phenomenon of aging was first observed by Sir Peter Medawar and was based on the concept of age-specific reproductive value of R A Fisher. Medawar’s mutation accumulation theory states that accumulation of late-acting deleterious alleles is due to decreased force of natural selection in older individuals, which is also referred to as ‘selection shadow’. A similar, but different, theory of aging known as antagonistic pleiotropy also describes the accumulation of alleles that are beneficial in early life, but deleterious in later life – the theory going that these harmful effects are moot in a wider sense, since when these genes are wreaking havoc, hopefully, offspring will have already been born and raised. However, the difference between the two theories is that in antagonistic pleiotropy, an evolutionary trade-off takes place between the fitness of young and old individuals while in mutation accumulation theory, the aging-associated alleles are uninvolved in young individuals [2].

Medawar also recognized the ambiguity regarding the term ‘aging’ which referred to any time-dependent change in a biological entity. This was different from ‘lifespan’ which referred to the age of death of an individual, and ‘senescence’ which referred to biological changes that yielded a higher probability of mortality as a function of age. Various large-scale genetic datasets and technological advances have recently shown renewed interest in the evolution of aging and the genetics of age-structured populations.

Insights from extreme agers of the animal kingdom

There is extraordinary variation among organisms on this planet. Such variations can help to analyze the evolution of the extreme ager trait and can provide information on the evolutionary trade-offs that might have led to this phenotype as well as the conditions under which they evolve.

The history of longevity

Evolutionary theory of aging predicts that lifespan will increase in organisms with low extrinsic mortality and decrease in organisms with high extrinsic mortality. Lifespan along with other life-history traits indicate that larger animals live longer, also termed allometric scaling. This suggests that short-lived species are smaller and have shorter maturation as well as generation times – one only has to consider a mouse vs an elephant to see this seems to be the case.

As per the common Gompertz hazard function, mortality increases exponentially with age. Although this has been considered to be a universal trait among most organisms, recent studies including amphibians, tortoises and non-avian reptiles have identified the rates of aging to be quite small or even negative. Some other species that show such negligible senescence include naked mole rats and rockfish. Several of these species exhibit indeterminate fertility and growth which could lead to such increased longevity. Other factors that may contribute to extreme lifespan include protective phenotypes, thermoregulatory mode, sex, temperature and metabolic rate.

Death and sex chromosomes

Significant sex differences in lifespan have been observed for many taxa, especially concerning the homogametic sex. This phenomenon could be due to the ‘unguarded X hypothesis’ which states that mutations in the X (or Z) chromosomes will be expressed only under a heterogametic context. An alternative explanation is the Y (or Z) chromosome becomes harmful with age due to misexpression and derepression of repetitive DNA. further studies have also indicated that the sizes of the X and Y chromosomes are associated with lifespan in mammals [2].

Comparative genomics of extreme aging

Novel long-read sequencing and genome assembly can help to interrogate long-lived wild species across the planet that could shed some light on the phenomenon of extreme aging.

Insights from genome assemblies

The complete genome of various extremely long-lived non-model species has been generated including the giant tortoises, bowhead whales, Asian and African elephants, the Canadian beaver and others. However, little attention has been given to short-lived species except the short-lived African turquoise killifish. Individual analysis of the genomes has indicated signatures of selection in key aging pathways including DNA repair, tumor-suppression pathways, cell cycle, inflammation, fatty acid metabolism and insulin signaling. In long-lived species, these pathways showed positive selection while in short-lived killifish it was rather relaxed. Similar signatures were also observed in the case of copy number and structural changes in the genome.

Insights from genome ensembles

Long-lived species were observed to have increased constraints in several aging pathways including immunity, cell death, cell cycle, insulin signaling and DNA repair. However, accumulation of deleterious mutations in similar pathways and small effective population sizes were observed in the case of short-lived killifish populations. This suggests that key aging pathways undergo strong selection in long-lived taxa, with individual innovation in select genes of individual species. These comparative approaches can have certain limitations such as reliability on large multiple sequence alignments (MSAs) which are expensive to generate and cannot describe genetic variation.

Insights from functional genomics

Functional characterization of genes and pathways identified in comparative genomics studies is important to understand the mechanisms that lead to differences in lifespan. Studies in elephants, bowhead whale, and their large-bodied relatives have shown a preference for repair mechanisms over the elimination of damaged cells.

The age-specific impacts of selection

A few strong variants that impact age-specific mortality in humans have been identified by Mostafavi et al [3]. These variants were observed to be CHRNA3 and APOE ε4, which may lead to smoking behavior and Alzheimer’s disease, respectively. Epidemiological studies have indicated an association between reproductive traits and female lifespan. Variants leading to decreased age at first birth in mothers and delay in puberty were observed to be associated with increased lifespan. On the contrary, coronary artery disease risk, cholesterol and body mass index (BMI) were associated with increased lifespan. Additionally, geographic and environmental factors as well as several genes have been reported to be some of the strongest predictors of lifespan.

Is mutation a cause and/or consequence of aging and death?

Mutation is the primary source of genetic variation. Research has highlighted that germline mutation rate increases with age. They also vary between species as per their life history and reproductive strategies. Moreover, a paternal bias in germline mutation rate was observed for mammals and birds but no such bias was observed for reptiles and fishes.

Positive association of age at maturity and generation time were observed to be positively associated with increased mutation rates. The difference in mutation spectrum was also observed between vertebrate classes, with the largest observed being A>C and C>A mutations in fish [2].

Somatic mutation

Somatic mutations are known to accumulate with age in all cells of the body. This accumulation is considered to be a hallmark of aging. It is difficult to identify somatic mutations due to their low frequency and difficulty in distinguishing them from artifactual sequencing errors. Somatic mutation rates often exceed their matched germline rates by 1–2 orders of magnitude which can be explained through the disposable soma theory.

Recent research has highlighted somatic mutation to have an inverse relationship with lifespan. Cancer is caused by somatic mutation, which suggests that larger organisms with a greater number of cells should be at a higher risk of developing cancer. This is indeed observed in certain cases for humans and dogs. However, there is contradictory research that indicates no correlation exists between body size, lifespan and cancer risk.

Evolving our understanding

The evolution of lifespan and aging is tightly linked with the evolution of mutation rates and processes. Rapid advancements have been made in understanding single-nucleotide mutations, but understanding of somatic and germline mutations remains incomplete. Future studies must focus on increasing our understanding of cellular aging across taxa which will provide better insights into the lifespan-associated pathways and explain their cell type-specific actions.

[1] https://www.sciencedirect.com/science/article/abs/pii/B9780123914989000085
[2] https://www.cell.com/trends/genetics/fulltext/S0168-9525(23)00186-5
[3] https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.2002458