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The germline DNA damage response actively truncates C. elegans lifespan

  • Author(s): Lister, Evan
  • Advisor(s): Cinquin, Olivier
  • et al.
Abstract

Lifespan varies dramatically between species, from weeks in the case of the nematode C. elegans to thousands of years in the case of the the conifer Pinus longaeva (bristlecone pine). What causes some organisms to live so briefly while others live for so long? The search for the answer to this question has resulted in the discovery of many experimental interventions that extend lifespan. One such intervention is the ablation of germ cells in the reproductive system. Lifespan control by the reproductive system has been demonstrated in C. elegans, in the fruit fly D. melanogaster, in the mouse species Mus musculus, and has even been suggested to apply to humans. This indicates that the effect of the reproductive system on lifespan may be conserved between invertebrates and mammals.

The various experimental interventions known to increase lifespan have been used to evaluate a range of theories on aging. These theories attempt to explain the cause of aging from either a molecular or an evolutionary angle. Lifespan control by the reproductive system may be particularly useful in evaluation of the evolutionary theories of aging. However, current knowledge of lifespan control by the reproductive system is incomplete. While a number of molecular intermediaries in this control have been identified, upstream signals are largely unknown. The result is a fundamental lack of understanding of why the reproductive system controls lifespan.

In this thesis, I identify the germline DNA damage response (DDR) as a possible driving force in the control of lifespan by the reproductive system. I find that levels of DDR activation rapidly increases with age in the germline of C. elegans. Increased germline DDR activation, effected by either targeted irradiation or genetic manipulation, leads to decreased lifespan. Conversely, the suppression of germline DDR through genetic means leads to increased lifespan. The checkpoint proteins ATM and ATR as well as insulin signaling play a central role in these lifespan effects.

The lifespan increase caused by reduced germline DDR does not come at the cost of decreased reproductive activity. This suggests that the disposable soma theory is insufficient to explain this lifespan effect. I propose a model in which germline DDR actively decreases lifespan as part of a mechanism to limit post-reproductive lifespan. Such a mechanism is consistent with the kin-selection theory of aging.

In addition to further elucidating the influence of the reproductive system on lifespan, I also demonstrate radiation hormesis in C. elegans through somatic cell irradiation. Previously reports have presented conflicting results when testing for radiation hormesis in worms, perhaps due to the obscuring effects of germline irradiation. My results demonstrate a reproducible way to increase lifespan by irradiation, opening the possibility of further investigation of the mechanism behind radiation hormesis using C. elegans as a model system.

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