Developmental Biology - Genetic Switches|
Would You Choose to Live Longer or Live Healthier?
Research in aging indicates 'quality of life' may be more important than 'length of life', as we age...
A surprising new genetic discovery from the University of Pittsburgh School of Medicine and UPMC Children's Hospital of Pittsburgh, Pennsylvania, suggests molecular switches may independently control lifespan and healthspan. The research is published in Nature Communications.
Healthspan is represented by parameters — like mobility and immune resistance — that are distinct from lifespan which can be easily measured.
Although harder to study, in the long run healthspan may be more important to modify, according to senior author Arjumand Ghazi. She describes the difference paraphrasing Greek mythology:
"The goddess Eos fell in love with a mortal, Tithonus, asking he be granted eternal life, forgetting to ask for eternal youth. Tithonus thus lived forever as a frail, immobile old man."
Currently, Ghazi and her team focus on the protein TCER-1 in their research on the worm Caenorhabditis elegans, or c. elegans. In earlier work, her lab showed TCER-1 promotes longevity in c. elegans and is critical to its fertility.
Longevity genes in many animals increase resistance to stressors, such as infection. So researchers expected removing TCER-1 would make the worms less resilient. Much to their surprise, they saw the exact opposite.
When infected with bacteria, subjected to DNA-damaging radiation or high temperature, worms without TCER-1 survived much longer than normal.
They also had improved mobility with age and were less prone to protein clumping that causes human neurodegenerative diseases.
To the contrary, increasing TCER-1 levels beyond normal suppressed an animal's immune defenses.
"I was sure I'd made a mistake somewhere," says Francis Amrit PhD, the study's lead author and a staff scientist in Ghazi's lab. "But, I repeated the experiments and realized that TCER-1 was unlike any other longevity gene we'd seen before — it was actually suppressing immune resistance."
Interestingly, TCER-1 seemed to be able to wield its influence only as long as the animals were young and capable of laying eggs.
"I liken TCER-1 in C. elegans to a DJ who controls the base, treble and other tones to get the music to sound just right," says Amrit. "During its reproductive age, TCER-1 tunes all the molecular dials to ensure that the animal reproduces efficiently to propagate the species, partly by diverting resources meant for stress management."
Ghazi cautions that it is too soon to make any conclusions about human healthspan, but notes that the finding should change how we understand the molecular basis of aging.
"It will be interesting to understand how the body allocates resources," Ghazi speculates. "For example, could women one day take a pill once they decide to stop having children that would improve their own healthspan by diverting resources used for reproduction toward improved stress resilience?"
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.
Francis R. G. Amrit, Nikki Naim, Ramesh Ratnappan, Julia Loose, Carter Mason, Laura Steenberge, Brooke T. McClendon, Guoqiang Wang, Monica Driscoll, Judith L. Yanowitz and Arjumand Ghazi.
The authors are grateful to Danielle Garsin (University of Texas Health Sciences Center, Houston) and K. Subramaniam (Indian Institute of Technology, Kanpur) for sharing strains, reagents, and methods. Thanks to Joseph Garvey (Carnegie Melon University) for assistance with strain generation and bacterial colonization assays. Some strains were provided by the CGC, which is funded by the NIH Office of Research Infrastructure Programs (P40 OD010440). This work was supported by a grant from the National Institutes of Health (R01AG051659) to A.G. and a post-doctoral fellowship from the New Jersey Commission on Cancer Research to G.W.
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Jul 23 2019 Fetal Timeline Maternal Timeline News
The goddess Eos gives mortal Tithonos eternal life, but not eternal youth, a scene painted on this vase circa 470–460 BC. Likewise in experiments, the gene TCER-1
improves mobility in worms paralyzed by toxic amyloid beta proteins, resetting all molecular switches to ensure it diverts all of its energy to managing stress - and living longer. Could humans do the same? CREDIT The Louvre.