Leading US gerontologists propose 12 molecular signals that can rapidly distinguish a drug that genuinely slows aging from an intervention that merely appears beneficial
Leading US gerontologists propose 12 molecular signals that can rapidly distinguish a drug that genuinely slows aging from an intervention that merely appears beneficial
On September 17, Steven Austad, Richard Miller, and Matt Kaeberlein published a review in Frontiers in Science analyzing data from the Interventions Testing Program (ITP), the federally funded mouse geroprotector trial (Miller is one of its directors). More than ten mouse models with confirmed decelerated aging, ranging from dietary interventions and genetic mutations to rapamycin, shared 12 common molecular shifts characteristic of "slow aging."
Proving in mice that a compound slows aging costs $100,000 to $300,000 and takes three to four years: the ITP can test only a small fraction of candidates, and roughly 15% of those tested so far have extended mouse lifespan.
Austad, Miller, and Kaeberlein (CEO of the biotech company Optispan) set out to find such a filter: a common denominator, a parameter that deviates from baseline in as many of these models as possible regardless of the direction of the shift. This yielded 12 indicators. A biomarker like an epigenetic clock is an odometer: the rate of change becomes visible only from measurements spaced years apart, as in the 24-year InCHIANTI cohort. The 12 indicators are designed as a speedometer, a signal of the current pace captured in a single measurement, even in a young animal.
The strongest result in the ITP database is the combination of rapamycin and acarbose: in males it increased median lifespan by 29%, in females by 22%. Rapamycin alone yields 23% in males and 26% in females.
Among the indicators are elevated levels of BDNF and doublecortin in the hippocampus (the brain's memory region): both protect neurons and stimulate the generation of new brain cells. Of the 12, only two can currently be measured in blood (irisin and GPLD1); the rest require tissue from the liver, adipose, brain, or muscle.
The same shift is also visible computationally: Richard Miller's model, trained on 1,051 plasma features from ITP mice, correctly predicted lifespan extension for five interventions withheld from training.
"The central challenge in translating the biology of aging into better health is understanding whether an intervention truly affects the rate of aging," Kaeberlein says. "Developing and validating indicators of the rate of aging would give us a tool to answer that question within a practical timeframe, rather than waiting years or decades for an effect on lifespan."
The authors see the path to humans running through dogs: the Dog Aging Project database already includes more than 50,000 pets, and a trial is underway to determine whether rapamycin extends their lifespan. The next step would be repeated blood analysis of people aged 55 to 60 at ten-year intervals, searching for analytes that predict the rate of subsequent change.
"A remarkable finding in mice is that many effective anti-aging drugs retain their full efficacy even when administration begins in late adulthood," says lead author Steven Austad. "Similar therapies may benefit middle-aged people."
The authors challenge prevailing frameworks in the field: they consider the canonical list of "hallmarks of aging" a subjective construct that channels funding toward convenient topics, and they regard the concept of "cellular senescence" as overvalued. Mice and dogs with long telomeres age in much the same way as humans with short telomeres, which runs counter to the telomere theory itself. They identify what they call gerontologiphobia as a brake on the field: a reluctance to study the slowing of aging itself, as distinct from treating its individual diseases.
By their calculation, complete elimination of all forms of cancer after age 50 would raise human median lifespan by only 2 to 3%, roughly ten times less than one combination of rapamycin and acarbose has already achieved in mice.