Self-amplifying signals from senescent cells drive the accelerating rise in mortality risk in old age, proposes the author of a theoretical paper in Aging

Self-amplifying signals from senescent cells drive the accelerating rise in mortality risk in old age, proposes the author of a theoretical paper in Aging

On October 20, Aging published a theoretical paper by Pierre-Edouard Sottas, co-founder of xLongevity, a company that operates longevity clinics. He divides aging into “burden” (slowly accumulating cellular damage) and “amplification” (signaling between cells that converts this burden into an accelerating rise in mortality risk).

Under the Gompertz law, human mortality risk doubles approximately every eight years, even though damage accumulates at a nearly constant rate. According to Sottas, models based solely on accumulating damage produce this curve only when they incorporate interactions between the body's subsystems or feedback between damage and repair, both of which provide amplification.

Sottas proposes that senescent cells drive this amplification. These cells have stopped dividing (a response that protects against cancer early in life), but they release inflammatory substances and extracellular vesicles, small membrane-bound sacs containing proteins and RNA. These signals cause other cells to become senescent and release the same signals, creating a self-sustaining feedback loop. The immune system, which clears senescent cells, and stem cells, which renew tissues, keep this loop in check. Sottas calls their combined ability to do so regenerative capacity, which declines with age. He builds on the hyperfunction theory of Mikhail Blagosklonny, the founder of Aging, and compares his distinction between burden and amplification with biologist David Gems's two-stage framework: growth programs that are beneficial early in life become harmful in old age and expose damage accumulated earlier.

Sottas bases his argument on the naked mole-rat, which has more oxidative damage than a mouse yet shows no age-related rise in mortality risk. In Calico's colony, an estimated 55,5 % of the animals survived to 35 years of age. He suggests that senescent cells in naked mole-rats die over time and therefore do not accumulate, leaving the feedback loop without a sustained source of signals.

In a computer model of this loop, reducing the rate at which damage enters the system, including through partial reprogramming (temporarily activating genes that rejuvenate cells), has its greatest effect early in life. In old age, it has little effect on feedback that is already established. Sottas writes of reprogramming:

“In terms of burden and amplification, reprogramming remains an intervention on the burden side, unless it also produces a lasting reduction in systemic amplification.”

In the same model, interventions that target the loop itself behave differently: drugs that clear senescent cells work best in old age, blood plasma exchange produces a partial and temporary effect, and increasing regenerative capacity (represented in the model by infusions of fluid in which cells have been cultured) suppresses senescence signals at any age.

For plasma exchange, the paper draws on a placebo-controlled trial involving 42 adults. In the group receiving plasma exchange and an antibody preparation, epigenetic age (an estimate based on chemical marks on DNA) fell by 2,6 years more than in the placebo group, but the difference disappeared at the next measurement. For infusions of the cell culture fluid, the paper cites only a pilot study co-authored by Sottas: after a 17-week program that included two infusions, epigenetic age in 14 participants was, on average, 2,7 years lower than before the program. xLongevity announces a service called “Systemic Signal Reset”: “fewer signals that promote aging, more regenerative signals.”

The author describes the most sustained form of rejuvenation as a state resembling “longevity escape velocity”: damage continues to accumulate, but feedback stays below the threshold for self-amplification, and mortality risk stops accelerating.