Longevity-Related Molecular Pathways Have Midlife Crisis

According to a study published today in Aging Cell, key molecular programs known to promote longevity do not last beyond midlife. The study provides a possible new reason why human disease burden increases so sharply from the sixth decade of life onward as health-protective mechanisms disappear.

"For over a decade, it has been clear that key biochemical events regulate the longevity of small short-lived animals such as worms, flies, and mice, but these mechanisms had not been observed to be active in humans," explained senior author Claes Wahlestedt, M.D., Ph.D., from the University of Miami Miller School of Medicine. "In this international clinical and genomic study, we report for the first time that humans use these same biochemical pathways during aging. Surprisingly, however, humans appear to stop using these pathways from about 50 years of age onward. Therefore, how long and how 'hard' each person regulates these pathways may influence human lifespan."

Using a novel RNA method to quantify tissue coding and long noncoding RNA (lncRNA), the team identified ~800 transcripts tracking with age up to ~60 years in human muscle and brain. Their novel observations in humans align well with previous work in short-lived species. This included a dominant role for the mTOR protein complex as well as mitochondrial reactive oxygen species production. These two cellular mechanisms combined to explain about two-thirds of the molecular aging profile in humans.

"Our study revealed that the complexity of regulation of aging programs may be much greater in humans as compared to other species," Dr. Wahlestedt said. "This is related to our more complex genome, which may have evolved to allow for longer and healthier lifespan. But perhaps humans were not really meant to last beyond their 50s."

From a molecular aging research perspective, humans are unique among species. Yet, like our shorter-lived distant relatives, the researchers also noted that, in humans, the molecular responses during aging don't follow a linear pattern. This counters an idea deeply entrenched in human epidemiology studies.

"Beyond the need to consider different 'phases' of molecular aging, clinical variables such as aerobic capacity and insulin resistance are also important to quantify," Dr. Timmons said. "They interact with some of the same genes as aging, are partly inherited, and are important predictors of health. We were able to look at these for the first time when modeling human aging."