Abstract
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.
Highlights
Stress resistance and longevity are positively correlated but emerging evidence indicates that they are physiologically distinct
Upon testing for resilience against the human opportunistic pathogen, P. aeruginosa PA14 strain ( PA14), using the Slow Killing (SK) paradigm, we found that tcer-1 mutants showed a dramatic increase in survival as compared to wild-type adults (Fig. 1a, Supplementary Table 1A, B)
Our results suggest that TCER-1 functions in a cell non-autonomous manner to influence both stress resistance and longevity, and it can act in any tissue to increase lifespan or reduce innate immunity
Summary
Stress resistance and longevity are positively correlated but emerging evidence indicates that they are physiologically distinct. This incomplete correlation implies that stress resistance alone is not sufficient to extend lifespan; other unknown process(es) may be induced coordinately with stress resistance in many long-lived mutants which may underlie their longevity These observations, and other emerging evidence, suggest that stress resilience is physiologically distinct from lifespan[9,10,11,12]. ATFS-1, SKN-1, HSF-1 and HIF-1, key mediators of UPRmt, OSR, HSR and HR, respectively, upregulate innate immunity genes and confer pathogen resistance[22,23,24,25,26] Many of these proteins, and other such stressresponse mediators, enhance lifespan in C. elegans and other species[22,23,27,28,29,30]. Under normal physiological conditions TCER-1 promotes reproductive fitness[37]
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