University at Buffalo Team Boosts a Single Protein, TTP, and Aging Mice Become Stronger, Less Inflamed and More Mobile Than Untreated Littermates

Aging mice given an extra dose of a single protein became markedly stronger, less inflamed and more mobile than untreated littermates, according to new University at Buffalo research that researchers say nudges the field one step closer to a therapy for the chronic, low-grade inflammation that drives much of human aging. The six-year study, funded by a $2.1 million National Institutes of Health grant and published in Aging and Disease, identifies the RNA-binding protein tristetraprolin, or TTP, as a central brake on inflammatory signaling — a brake that wears out as animals get old.

The team, led by senior author Bruce Troen of UB's Jacobs School of Medicine and Biomedical Sciences, used a transgenic mouse line engineered to maintain stable TTP expression as the animals aged, rather than letting the protein decline as it typically does after middle age. By the time the mice reached 22 months — equivalent to roughly the late 70s in humans — the TTP-boosted animals outperformed controls on grip strength, walking speed, treadmill endurance and rotarod balance tests. They also showed denser bone, lower circulating concentrations of the inflammatory cytokine IL-6, and a lower incidence of age-related kidney scarring.

"The increase in TTP resulted in better grip strength, better walking, endurance and overall physical performance," Troen said in a UB press release. "What is striking is that we did not change diet, exercise or any other behaviour. We simply asked the body to keep doing what it already does well in youth, for longer." TTP works by destabilizing the messenger RNA of dozens of pro-inflammatory genes, ensuring that when an inflammatory response launches it also winds down on schedule. Aging cells make less TTP, the team showed, and the inflammatory response lingers — a pattern researchers have begun calling "inflammaging."

The paper joins a fast-growing list of papers identifying single-protein targets that look like nodes in the aging process. Stanford researchers reported in April that an enzyme called eEF1A2 in the brain drives memory loss when its levels climb in old animals. Harvard's David Sinclair group has spent more than a decade chasing sirtuins and NAD+ precursors. The Buffalo work is unusual in that it shows a direct, immediate functional improvement in elderly mice without any sign of premature death or tumour formation in the treated animals during the study window.

Whether TTP can be safely boosted in humans is the obvious next question. Direct genetic intervention is not feasible in adults, but Troen's lab is screening small molecules that stabilize the protein's own degradation cycle, and a separate group at Duke is developing an mRNA therapeutic that delivers TTP transcripts directly to muscle. Both efforts are years from human trials. "Aging is not one disease and there will never be one pill," Troen said. "But we now have a credible target, and the older you are when you intervene, the bigger the apparent benefit was in our mice. That's the surprise of this study."