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Aging is a complex process that results in loss of the ability to reattain homeostasis following stress, leading, thereby, to increased risk of morbidity and mortality. Many factors contribute to aging, such as the time-dependent accumulation of macromolecular damage, including DNA damage. The integrity of the nuclear genome is essential for cellular, tissue, and organismal health. DNA damage is a constant threat because nucleic acids are chemically unstable under physiological conditions and vulnerable to attack by endogenous and environmental factors. To combat this, all organisms possess highly conserved mechanisms to detect and repair DNA damage. Persistent DNA damage (genotoxic stress) triggers signaling cascades that drive cells into apoptosis or senescence to avoid replicating a damaged genome. The drawback is that these cancer avoidance mechanisms promote aging. Here, we review evidence that DNA damage plays a causal role in aging. We also provide evidence that genotoxic stress is linked to other cellular processes implicated as drivers of aging, including mitochondrial and metabolic dysfunction, altered proteostasis and inflammation. These links between damage to the genetic code and other pillars of aging support the notion that DNA damage could be the root of aging.

Extreme environments test the limits of life; yet, some organisms thrive in harsh conditions. Extremophile lineages inspire questions about how organisms can tolerate physiochemical stressors and whether the repeated colonization of extreme environments is facilitated by predictable and repeatable evolutionary innovations. We identified the mechanistic basis underlying convergent evolution of tolerance to hydrogen sulfide (H₂S)—a toxicant that impairs mitochondrial function—across evolutionarily independent lineages of a fish (Poecilia mexicana, Poeciliidae) from H₂S-rich springs. Using comparative biochemical and physiological analyses, we found that mitochondrial function is maintained in the presence of H₂S in sulfide spring P. mexicana but not ancestral lineages from nonsulfidic habitats due to convergent adaptations in the primary toxicity target and a major detoxification enzyme. Genome-wide local ancestry analyses indicated that convergent evolution of increased H₂S tolerance in different populations is likely caused by a combination of selection on standing genetic variation and de novo mutations. On a macroevolutionary scale, H₂S tolerance in 10 independent lineages of sulfide spring fishes across multiple genera of Poeciliidae is correlated with the convergent modification and expression changes in genes associated with H₂S toxicity and detoxification. Our results demonstrate that the modification of highly conserved physiological pathways associated with essential mitochondrial processes mediates tolerance to physiochemical stress. In addition, the same pathways, genes, and—in some instances—codons are implicated in H₂S adaptation in lineages that span 40 million years of evolution.

Hydrogen sulfide (H2S) is well known as a toxic gas produced by the decomposition of organic matter and geothermal sources and also produced endogenously by cysteine catabolism. Exposure to H 2S drives hormetic effects including toxic inhibition of cytochrome c oxidase of the mitochondrial electron transport chain at high concentrations, and maintenance of normal vascular and neural functions at low concentrations. Abnormal elevation of cellular H2S, due to either environmental exposure or defective detoxification, is correlated with vascular and metabolic dysfunction in most aerobic organisms, however Poecilia mexicana thrives in H2S rich environments. The cellular mechanisms whereby organisms tolerate extreme H2S are not fully understood. Our central hypothesis is that sulfide tolerant fish have an enhanced H 2S detoxification capacity and/or resistance to H2S toxicity following exposure, relative to non-tolerant fish. Specifically, we hypothesized that sulfide tolerant fish differentially express genes involved in maintaining H2S homeostasis. We found significant differences in gene expression patterns related to H2S detoxification between lab-reared sulfide tolerant and non-tolerant populations originating from the Tacotalpa drainage. Since mitochondria are both the site of H2S toxicity as well as enzymatic detoxification, we further hypothesized that tolerance is achieved by modifications to mitochondrial respiration. To test this, we compared mitochondrial function between 1) lab-reared and wild captured sulfide tolerant and non-tolerant populations originating from Tacotalpa drainage and 2) wild captured sulfide tolerant and non-tolerant populations originating from the Puyacatengo and Pichucalco drainages. We predicted that sulfide tolerant fish are able to maintain mitochondrial respiration in the presence of increasing concentrations of H2S relative to non-tolerant fish and that the sulfide tolerant population captured from Pichucalco drainage, which has the highest concentration of environmental H2S compared to other drainages tested, would exhibit the greatest degree of H2S tolerance compared to the sulfide tolerant populations from drainages with lower environmental H2S. We determined that mitochondria from sulfide tolerant fish have increased maximal and spare respiratory capacities following exposure to high concentrations of H2S, relative to non-tolerant fish, and that the population captured from Pichucalco exhibits the greatest degree of tolerance compared to the other two drainages.

Extreme environments test the limits of life. Still, some organisms thrive in harsh conditions, begging the question whether the repeated colonization of extreme environments is facilitated by predictable and repeatable evolutionary innovations. We identified the mechanistic basis underlying convergent evolution of tolerance to hydrogen sulfide (H2S) - a potent toxicant that impairs mitochondrial function - across evolutionarily independent lineages of a fish (Poecilia mexicana, Poeciliidae) from H2S-rich freshwater springs. We found that mitochondrial function is maintained in the presence of H2S in sulfide spring P. mexicana, but not ancestral lineages in adjacent nonsulfidic habitats, due to convergent adaptations in both the primary toxicity target and a major detoxification enzyme. Additionally, we show that H2S tolerance in 10 independent lineages of sulfide spring fishes across multiple genera of Poeciliidae is mediated by convergent modification and expression changes of genes associated with H2S toxicity and detoxification. Our results demonstrate that the repeated modification of highly conserved physiological pathways associated with essential mitochondrial processes enabled the colonization of novel environments. Footnotes * https://github.com/michitobler/convergent_h2s_evolution