A longevity news story breaking today was widely published in the world press. Some of the 123 headlines listed on Google are Ageing Process “reversed” in mice, Die hard: Scientists reverse aging in mice Scientists unlock secret of eternal youth Secret to eternal youth ‘found’, Harvard scientists reverse aging in mice Virility, Mental Ability Restored in Aged Mice in Gene Study,Nature Says, Science Makes Old Mice Young Again Scientists Find Fountain of Youth … in Mice Harvard University Doctor Turns Back Time on Aging: Will an Anti-Aging Pill Be .., Enzyme Reverses Aging in Mice andThe Curious Case of the Backwardly Aging Mouse.
I think the research reported is quite important though these headlines sensationalize and misrepresent that research. I comment here both on the research and on the press coverage it received.
The publication that initiated this press flurry is a 28 November online publication that appeared in Nature Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. “An ageing world population has fuelled interest in regenerative remedies that may stem declining organ function and maintain fitness. Unanswered is whether elimination of intrinsic instigators driving age-associated degeneration can reverse, as opposed to simply arrest, various afflictions of the aged. Such instigators include progressively damaged genomes. Telomerase-deficient mice have served as a model system to study the adverse cellular and organismal consequences of wide-spread endogenous DNA damage signalling activation in vivo. Telomere loss and uncapping provokes progressive tissue atrophy, stem cell depletion, organ system failure and impaired tissue injury responses1. Here, we sought to determine whether entrenched multi-system degeneration in adult mice with severe telomere dysfunction can be halted or possibly reversed by reactivation of endogenous telomerase activity. To this end, we engineered a knock-in allele encoding a 4-hydroxytamoxifen (4-OHT)-inducible telomerase reverse transcriptase-oestrogen receptor (TERT-ER) under transcriptional control of the endogenous TERT promoter. Homozygous TERT-ER mice have short dysfunctional telomeres and sustain increased DNA damage signalling and classical degenerative phenotypes upon successive generational matings and advancing age. Telomerase reactivation in such late generation TERT-ER mice extends telomeres, reduces DNA damage signalling and associated cellular checkpoint responses, allows resumption of proliferation in quiescent cultures, and eliminates degenerative phenotypes across multiple organs including testes, spleens and intestines. Notably, somatic telomerase reactivation reversed neurodegeneration with restoration of proliferating Sox2+ neural progenitors, Dcx+ newborn neurons, and Olig2+ oligodendrocyte populations. Consistent with the integral role of subventricular zone neural progenitors in generation and maintenance of olfactory bulb interneurons2, this wave of telomerase-dependent neurogenesis resulted in alleviation of hyposmia and recovery of innate olfactory avoidance responses. Accumulating evidence implicating telomere damage as a driver of age-associated organ decline and disease risk and the marked reversal of systemic degenerative phenotypes in adult mice observed here support the development of regenerative strategies designed to restore telomere integrity.”
So, mice were genetically engineered to be born with knocked-out telomerase genes and these mice aged in an accelerated fashion They eventually exhibited most or all the degenerative conditions known to be associated with aging. Such effects have been observed for many years. The new discovery is that reactivation of telomerase in these mice reverses many of the phenomena of aging and, in effect, makes these mice younger again. This is an extremely important discovery because it strongly suggests that a single intervention can reverse the multiple deleterious manifestations of aging which have always been thought to be permanent and, once occurred, irreversible. At least this seems to be true for aging induced by telomerase deficiency. To me it comes close to being a mind-boggling proof-of-concept that aging can be reversed, establishing that aging is a two-way street. It is also additional evidence that aging is not just due to accumulation of random damage due to wear-and tear. It would be impossible to repair so many and so radically different forms of random damage with a single intervention.
The writeup in Nature News is more plain-spoken. “ — When mice are engineered to lack telomerase completely, their telomeres progressively shorten over several generations. These animals age much faster than normal mice — they are barely fertile and suffer from age-related conditions such as osteoporosis, diabetes and neurodegeneration. They also die young. “If you look at all those data together, you walk away with the idea that the loss of telomerase could be a very important instigator of the ageing process,” says DePinho (Ronald DePinho, an author of the research publication and a cancer geneticist at the Dana-Farber Cancer Institute and Harvard Medical School). — To find out if these dramatic effects are reversible, DePinho’s team engineered mice such that the inactivated telomerase could be switched back on by feeding the mice a chemical called 4-OHT. The researchers allowed the mice to grow to adulthood without the enzyme, then reactivated it for a month. They assessed the health of the mice another month later. — “What really caught us by surprise was the dramatic reversal of the effects we saw in these animals,” says DePinho. He describes the outcome as “a near ‘Ponce de Leon’ effect” — a reference to the Spanish explorer Juan Ponce de Leon, who went in search of the mythical Fountain of Youth. Shrivelled testes grew back to normal and the animals regained their fertility. Other organs, such as the spleen, liver and intestines, recuperated from their degenerated state. — The one-month pulse of telomerase also reversed effects of ageing in the brain. Mice with restored telomerase activity had noticeably larger brains than animals still lacking the enzyme, and neural progenitor cells, which produce new neurons and supporting brain cells, started working again. — “It gives us a sense that there’s a point of return for age-associated disorders,” says DePinho. Drugs that ramp up telomerase activity are worth pursuing as a potential treatment for rare disorders characterized by premature ageing, he says, and perhaps even for more common age-related conditions. – “
Let me turn to the sensationalism in the press reporting for a moment. If you have read my recent blog post When reading press releases and newspaper articles about research discoveries, beware! then you know I am sensitive to misrepresentation of research results in headlines. I hate to be nitpicking but most of the press reports for this research do not make clear:
1. The study shows only that accelerated aging from one cause can be reversed, that cause being lack of telomerase expression. We know that many causes can accelerate apparent aging (like exposure to radiation and some chemicals) but we do not know yet whether aging from such causes can be reversed. And we do not know if natural aging, however that comes about, can be reversed. I hope and suspect that aging-is-aging and aging from all causes can be reversed, but as a scientist I don’t know yet that this is true.
2. The apparent age reversal observed was not in normal mice who aged normally. It was in mice genetically engineered not to have a natural feature, an active telomerase gene, who age (or do something very much like aging) prematurely. The age-reversal was initiated by restoring what had been taken away, natural telomerase production. We do not know if the age reversal would work in normally aged mice let alone in normally-aged humans.
3. Despite the fact that telomerase-deficient mice age more rapidly, neither this work nor any other research I know about establishes that telomere-lengths are critical for limiting normal lifespans in either mice or humans. It was not reported that the mutant mice who underwent age-reversal lived longer than normal mice. There is no indication that extended lifespan let alone eternal youth was involved despite the headlines claiming it.
4. The genetic-engineering approach to turning the telomerase genes back on in the mutant mice can’t be used in humans since any genetic engineering of humans is taboo.
“Harrison (David Harrison, who researches ageing at the Jackson Laboratory in Bar Harbor, Maine) also questions whether mice lacking telomerase are a good model for human ageing. “They are not studying normal ageing, but ageing in mice made grossly abnormal,” he says. Tom Kirkwood, who directs the Institute for Ageing and Health at Newcastle University, UK, agrees, pointing out that telomere erosion “is surely not the only, or even dominant, cause” of ageing in humans(ref).”
So, while this research is important and very encouraging from the viewpoint of life extension, it is not at all clear that it will lead to life-extending interventions in humans. I agree with DePinho who “says he recognizes that there is more to ageing than shortened telomeres, particularly late in life, but argues that telomerase therapy could one day be combined with other therapies that target the biochemical pathways of ageing. “This may be one of several things you need to do in order to extend lifespan and extend healthy living,” he says(ref).”
For background you can read about the Telomere Shortening and Damage theory of aging in my treatise. For updates on recent research on telomerase, you can see my recent blog entries: