Review
Sex-specific regulation of aging and apoptosis

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Abstract

Genetic analysis of Drosophila, mice and humans indicates that gene alleles, mutations and transgenes that affect life span tend to do so differently depending on the sex of the organism. The likely reason for this is that the sexes are different genotypes (e.g., X/X vs. X/Y) and face quite different environments: e.g., to reproduce, males have to mate with females while females have to mate with males. Genes are subject to different genetic interactions and different gene-by-environment effects in male vs. female. The consequence is that through evolution certain genes are differently selected and optimized for each sex. Both the mitochondrial genome and the X chromosome are asymmetrically inherited in Drosophila and mammals; through evolution these genes spend relatively more time under selection in females and are therefore expected to be better optimized for function in the female than in the male. Consistent with this the Drosophila X chromosome has been found to be a hotspot for sexually antagonistic fitness variation. Old Drosophila and old mammals exhibit apoptosis—an observation consistent with the idea that the mitochondria are less functional during aging due to maternal-only inheritance. One feature of aging that is common to Drosophila and mammals is that females tend to live longer than males, and this may be due in part to sub-optimal mitochondrial function in males. The data support the conclusion that a significant part of the aging phenotype is due to antagonistic pleiotropy of gene function between the sexes. Liberal application of Occam's razor yields a molecular model for the co-regulation of sex, apoptosis and life span based on the on/off status of a single gene: Sxl in Drosophila melanogaster and Xist in humans. Aging may simply represent an ancient and conserved mechanism by which genes re-assort.

Introduction

Recent and classic observations suggest an important and ancient role for the mitochondria in the determination of the germ-line/soma distinction and sexual identity. A defining feature (and I would argue, the defining feature) of the oocyte is its asymmetric inheritance of the mitochondrial genomes. Asymmetric inheritance of mitochondrial genes and sex chromosome genes promotes the evolution of sexually antagonistic gene functions. Genes exhibiting such antagonistic pleiotropy (compromised function in one sex or both) are expected to contribute preferentially to the aging phenotype. In this review I try to relate these diverse topics and create a logical framework through which our embryonic understanding of gametogenesis and mitochondrial segregation can be used to predict which genes and molecular processes are most likely to regulate the functional life span of the organism.

Section snippets

Aging and life span

Aging in living organisms is more correctly termed senescence, and is generally described as a cumulative, irreversible process resulting in decreased function and increased risk of death. Aging of some kind appears to affect all living organisms, from bacteria to humans (Ackermann et al., 2003, Stewart et al., 2005). How long an individual lives – its life span – is characteristic of different species (Finch, 1990): Drosophila can live 100 days, humans can live 100 years. Within each species

Evolutionary theory of aging

Like all things biological, aging and life span are shaped by genes and evolution (Kirkwood and Austad, 2000). Natural selection efficiently removes deleterious mutations from the population. However, a mutation that causes a problem only at late ages is not efficiently removed. For example, a human gene allele that predisposes individuals to Alzheimer's or Parkinson's disease is not efficiently removed from the population because by the time the disease is manifested the gene has usually

Asymmetric gene inheritance—a battle of the sexes

Antagonistic pleiotropy, as described above, refers to gene alleles that are beneficial at an early age and deleterious at a late age. Another type of antagonistic pleiotropy is between the sexes: a gene allele that benefits one sex of the species can be relatively deleterious to the other sex (Rice, 1992, Rice, 1998, Chippindale et al., 2001). This is possible because the sexes have different genotypes (e.g., X/X vs. X/Y), different environments (e.g., unique genital tract microbial fauna) and

Mitochondrial asymmetric inheritance

Mitochondria are asymmetrically inherited (maternal inheritance only), meaning natural selection acting on the mitochondrial genome (mitogenome or M) and the mitogenome-nuclear genome interactions is effective only in females (Fig. 1) (Rand et al., 2001, Rand et al., 2006, Rand, 2005). In other words, the mitochondrial genome is optimized for function in the female. The male is therefore inherently less fit because the highly beneficial mitochondrial genome is not optimized for his genome. This

Apoptosis

In addition to energy production, mitochondria have another critical function. Apoptosis is a form of active cellular suicide involving characteristic morphological changes such as membrane blebbing. It functions to remove cells that are otherwise unwanted, such as in the developmental sculpting of human fingers and Drosophila gut, or dangerous, such as virally infected cells (Baehrecke, 2002, Baehrecke, 2003, Cashio et al., 2005, Yin and Thummel, 2005). An evolutionarily conserved set of

The mitochondria and apoptosis in gametogenesis

Mitochondria exhibit striking behaviors in germ cells that have generally been interpreted to be a result of the requirement for transmitting healthy mitochondria to the next generation, and the presumed high energy demand of sperm motility and the dramatic transformations associated with spermatogenesis. However, the role of the mitochondria in male and female gametogenesis extends far beyond the mere production of energy.

Mitochondria play a central role in the differentiation of the gametes

Evolution—the benefit of battle

The asymmetric inheritance of the M, X and Y chromosomes creates abundant opportunities for antagonistic pleiotropy of gene function between the sexes. This sets up a situation of balancing competition and selection between the male and female that is thought to benefit both because it promotes genetic diversity—sometimes called a Red Queen situation (Nowak and Sigmund, 2004). It is possible to envision this situation as a driving force in eukaryotic evolution: the male is inherently less fit

Life span QTLs

Quantitative trait loci (QTLs) are regions of the chromosome that are associated with differences in a scalable phenotype such as bristle number or life span. Life span QTLs can be identified based on the general strategy of crossing a short-lived strain with a long-lived strain, deriving sub-strains of varying life span, and correlating specific chromosomal genetic markers with shorter or longer life span across strains. This strategy works quite well in organisms such as Drosophila, C. elegans

Life span mutations and transgenes

A number of single-gene mutations have been identified that can increase Drosophila life span (Helfand and Rogina, 2003, Ford and Tower, 2006). Where tested most appear to affect both male and female, although there is often a bias in effect for one sex or the other (Burger and Promislow, 2004).

The antioxidant enzyme Cu/ZnSOD is found in the cytoplasm and outer mitochondrial space in most eukaryotic cells (Landis and Tower, 2005). Ubiquitous over-expression of Cu/ZnSOD in Drosophila was found

Oxidative stress and apoptosis in old animals

A large body of data demonstrates a correlation between mitochondrial misfunction, oxidative stress and aging across species (Walter et al., 1998, Hekimi and Guarente, 2003, Fridovich, 2004, Landis and Tower, 2005, Wallace, 2005). During aging oxidatively damaged macromolecules and abnormal mitochondria increase in concentration and oxidative stress-response genes are expressed in tissue-specific patterns. These observations appear to apply generally to both males and females of Drosophila,

Does apoptosis limit or regulate life span?

The observation of apoptotic events in old animals begs the question of whether this process limits life span. Results of a genetic screen support a role for apoptosis in Drosophila life span regulation (Fig. 2). Previously, 10,000 male flies were generated where each fly had at least one new insertion of an engineered P transposable element called PdL (Landis et al., 2003). PdL contains an outwardly directed, doxycycline(DOX)-regulated promoter at its 3′ end, that can drive over-expression of

A binary switch model for sex determination, apoptosis and life span

A molecular model consistent with the data and evolutionary theories can be constructed using a binary switch—the on/off status of a gene that regulates mitochondrial genome maintenance. The mitochondrial genome is asymmetrically inherited—meaning that some mechanism exists to ensure that mitochondrial genomes are present and inherited through the cytoplasm of the oocyte and are (almost) never inherited through the sperm, as discussed above. Therefore, asymmetric segregation is accomplished by

Why is apoptosis the default state for the mitochondria?

A variety of genes, both nuclear and mitochondrial, co-exist in the cell to their mutual benefit and thereby optimize their survival, replication and transmission to the next generation. Genetic variation and selection are the basis for evolution as we know it. For variation and selection to occur, genes must give rise to new alleles and these alleles must in turn segregate or otherwise re-assort—i.e., come apart and re-unite in different combinations. From the point of view of any given gene

Asymmetric segregation of genes as an evolutionary force

The general strategy of finite half-life creating asymmetric segregation could be an ancient and important one in evolution. Consider a primordial gene A that encodes a replicator molecule that replicates gene A (Fig. 6). A and its product might be floating around free in the primordial soup, or be surrounded by the membrane of a proto-cell (Szathmary, 2000, Hogeweg and Takeuchi, 2003, Scheuring et al., 2003, Line, 2005). Another gene B could cooperate with and be linked to A (either covalently

The mitochondrial apple?

In Biblical history the snake tempts Eve into eating an apple from the forbidden tree of knowledge. Adam and Eve become aware of their nakedness and in retribution God casts them out of the Garden of Eden forever. When the proto-eukaryotic female ingested the highly beneficial mitochondrial genome and maintained it through asymmetric inheritance, she introduced an asymmetry in fitness between the sexes. The resultant antagonistic pleiotropy of gene function between male and female helped drive

Acknowledgements

I thank the following for help doing research: Gary Landis, Morris Waskar, Yishi Li, Jie Shen, Diana Abdueva, Dmitriy Skvortsov, and Christina Curtis; and thank Michelle Arbeitman, Steve Finkel, Dan Ford, Simon Tavaré, Tuck Finch and the anonymous reviewers for critical and insightful comments on the manuscript. This work was supported by grants from the Department of Health and Human Services (AG11833, AG11644) and a Sr. Scholar Award from the Ellison Medical Foundation.

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