Molecular basis of reproductive senescence: insights from model organisms.

PURPOSE: Reproductive decline due to parental age has become a major barrier to fertility as couples have delayed having offspring into their thirties and forties. Advanced parental age is also associated with increased incidence of neurological and cardiovascular disease in offspring. Thus, elucidating the etiology of reproductive decline is of clinical importance. METHODS: Deciphering the underlying processes that drive reproductive decline is particularly challenging in women in whom a discrete oocyte pool is established during embryogenesis and may remain dormant for tens of years. Instead, our understanding of the processes that drive reproductive senescence has emerged from studies in model organisms, both vertebrate and invertebrate, that are the focus of this literature review. CONCLUSIONS: Studies of reproductive aging in model organisms not only have revealed the detrimental cellular changes that occur with age but also are helping identify major regulator proteins controlling them. Here, we discuss what we have learned from model organisms with respect to the molecular mechanisms that maintain both genome integrity and oocyte quality.

Meiotic dysfunction accelerates somatic aging in Caenorhabditis elegans.

An expanding body of evidence, from studies in model organisms to human clinical data, reveals that reproductive health influences organismal aging. However, the impact of germline integrity on somatic aging is poorly understood. Moreover, assessing the causal relationship of such an impact is challenging to address in human and vertebrate models. Here, we demonstrate that disruption of meiosis, a germline restricted process, shortened lifespan, impaired individual aspects of healthspan, and accelerated somatic aging in Caenorhabditis elegans. Young meiotic mutants exhibited transcriptional profiles that showed remarkable overlap with the transcriptomes of old worms and shared similarities with transcriptomes of aging human tissues as well. We found that meiosis dysfunction caused increased expression of functionally relevant longevity determinants whose inactivation enhanced the lifespan of normal animals. Further, meiotic mutants manifested destabilized protein homeostasis and enhanced proteasomal activity partially rescued the associated lifespan defects. Our study demonstrates a role for meiotic integrity in controlling somatic aging and reveals proteostasis control as a potential mechanism through which germline status impacts overall organismal health.

Auxin treatment increases lifespan in Caenorhabditis elegans.

The auxin-inducible degradation system (AID) has proven to be a highly versatile technology for rapid, robust and reversible depletion of proteins in multiple model systems. In recent years, AID has been adapted into the nematode Caenorhabditis elegans as a tool for conditional protein knockdown. Numerous transgenic strains have been created that, upon auxin exposure, undergo protein inactivation in the worm germline or somatic tissues, both during development and in young adults. Since longevity assays often involve long-term gene- and protein-manipulation, the facility for spatiotemporally precise and extended protein removal makes AID a potentially highly valuable tool for aging biology. However, whether auxins themselves impact worm longevity has not been directly addressed. Here, we show that prolonged exposure to indole 3-acetic acid (IAA), the auxin used in worm AID studies, extends lifespan. We also report that two transgenic strains expressing Arabidopsis proteins that are key components of the AID platform are longer lived than wild-type animals. Together, our results highlight the necessity for exercising caution while utilizing AID for longevity studies and in interpreting the resulting data. This article has an associated First Person interview with the first author of the paper.

Cell nonautonomous roles of NHR-49 in promoting longevity and innate immunity.

Aging and immunity are inextricably linked and many genes that extend life span also enhance immunoresistance. However, it remains unclear whether longevity-enhancing factors modulate immunity and longevity by discrete or shared mechanisms. Here, we demonstrate that the Caenorhabditis elegans pro-longevity factor, NHR-49, also promotes resistance against Pseudomonas aeruginosa but modulates immunity and longevity distinctly. NHR-49 expression increases upon germline ablation, an intervention that extends life span, but was lowered by Pseudomonas infection. The immunosusceptibility induced by nhr-49 loss of function was rescued by neuronal NHR-49 alone, whereas the longevity diminution was rescued by expression in multiple somatic tissues. The well-established NHR-49 target genes, acs-2 and fmo-2, were also differentially regulated following germline elimination or Pseudomonas exposure. Interestingly, neither gene conferred immunity toward Gram-negative Pseudomonas, unlike their known functions against gram-positive pathogens. Instead, genes encoding antimicrobial factors and xenobiotic-response proteins upregulated by NHR-49 contributed to resistance against Pseudomonas. Thus, NHR-49 is differentially regulated by interventions that bring about long-term changes (life span extension) versus short-term stress (pathogen exposure) and in response it orchestrates discrete outputs, including pathogen-specific transcriptional programs.

The longevity-promoting factor, TCER-1, widely represses stress resistance and innate immunity.

Stress resistance and longevity are positively correlated but emerging evidence indicates that they are physiologically distinct. Identifying factors with distinctive roles in these processes is challenging because pro-longevity genes often enhance stress resistance. We demonstrate that TCER-1, the Caenorhabditis elegans homolog of human transcription elongation and splicing factor, TCERG1, has opposite effects on lifespan and stress resistance. We previously showed that tcer-1 promotes longevity in germline-less C. elegans and reproductive fitness in wild-type animals. Surprisingly, tcer-1 mutants exhibit exceptional resistance against multiple stressors, including infection by human opportunistic pathogens, whereas, TCER-1 overexpression confers immuno-susceptibility. TCER-1 inhibits immunity only during fertile stages of life. Elevating its levels ameliorates the fertility loss caused by infection, suggesting that TCER-1 represses immunity to augment fecundity. TCER-1 acts through repression of PMK-1 as well as PMK-1-independent factors critical for innate immunity. Our data establish key roles for TCER-1 in coordinating immunity, longevity and fertility, and reveal mechanisms that distinguish length of life from functional aspects of aging.