Life without Twinkies – Calorie restriction and Telomerase

The bottom line of this post, for readers who do not have time for the long version, is this. In animal models, telomerase activation is required to extend lifespan. Caloric restriction by itself, in the most carefully controlled rodent studies, does not extend lifespan in the absence of telomerase activation. The combination of the two appears to do something that neither does alone.

Here is the longer version.

The early telomerase work

Three or four foundational studies established that telomerase activity is the rate-limiting factor in cellular longevity, at least in mammalian systems. The earliest of these came out of Jerry Shay’s lab in Texas in the late 1990s. The Shay group introduced telomerase into healthy human somatic cells using oncogene promoters. The cells, which would normally have hit replicative senescence after a few dozen divisions, just kept dividing. The experiment ended not because the cells got sick, but because the lab ran out of patience and budget. The cells exceeded the normal replicative limit by a factor of roughly seven, with no signs of cancerous transformation. Healthy cells, when given enough telomerase, behave as functionally immortal cells without becoming cancer cells.

The takeaway from that work is straightforward. Add sufficient telomerase activity to a healthy cell, and you can extend its functional life dramatically. Telomerase is necessary. It is not, in healthy cells, sufficient to cause cancer.

The Blasco lab work

Maria Blasco’s group at the Spanish National Cancer Centre has run the most comprehensive series of in vivo telomerase activation experiments in mammals. Two findings are worth highlighting.

First, Blasco’s group developed delivery of the telomerase gene using an adeno-associated virus vector, specifically AAV9. AAV9 has two properties that matter for this work. It infects a wide range of tissue types, so the telomerase reaches many cell populations. And it does not integrate into the host genome, so its effects dilute out over cell divisions rather than driving permanent transgene expression. That non-integration property addressed the cancer concern that had limited earlier attempts at germline telomerase transgenes.

The results were notable. Mice treated with AAV9-telomerase in middle age lived roughly 24 percent longer than untreated controls. Mice treated in old age lived roughly 14 percent longer. No increase in cancer incidence was observed. Bone density, fat-free mass, glucose tolerance, neuromuscular coordination, and other functional measures of aging all improved in the treated animals.

Second, in the most recent paper out of the Blasco lab, the group looked at the interaction between caloric restriction and telomerase activation. Caloric restriction alone, in their mouse model, did not extend maximum lifespan, though it did improve neurologic and metabolic parameters and reduce cancer incidence. Telomerase activation alone extended lifespan. The combination, telomerase activation plus caloric restriction, produced the lifespan extension with reduced cancer incidence relative to telomerase alone.

Why this matters for humans

Two things to take from this.

One. Caloric restriction is not the longevity intervention it has been marketed as in mammals. It improves some metabolic markers. It does not, by itself, extend lifespan in carefully controlled studies. The CR enthusiasm of the 2000s has been quietly walked back by much of the field.

Two. Telomerase activation does extend lifespan in mammals. The relevant question for humans is whether we can achieve enough telomerase activation, safely, to capture some fraction of the rodent benefit. TA-65 is the most studied compound in this category in humans, with safety and efficacy data on reduction of critically short telomeres, immune profile changes, and other age-related markers. The effect size in humans is smaller than what gene-therapy approaches produce in mice. It is also achievable today, without a viral vector.

The animal data also gives us a reasonable framework. Mice treated earlier, in middle age, did better than mice treated late. That argues for not waiting until old age to start.

The cancer question

The cancer concern with telomerase activation has been raised repeatedly since the field began. The data so far, in both animal models with AAV9-telomerase and in long-running human use of TA-65, has not shown an increase in cancer incidence. The mechanism that was originally feared, telomerase enabling cancer cells to escape replicative senescence, is real in cancer cells. But cancer cells already have telomerase activity through other mechanisms, and adding modest telomerase activation to healthy cells has not been shown to drive transformation in the studies done to date.

It is a question worth continuing to study. It is not, at this point, a reason to avoid prudent telomerase support in adults.

— Doc