Considering Efforts to Repair the Signs of Aging

The research team who recently assessed the effects of FOXO4-DRI on clearing senescent cells here publish a short commentary on the broader scope of targeting the causes of aging for repair. Note that the commentary is available in PDF format only at this point. It is good to see more scientists, and even some of the more conservative voices in the research community talking openly on this topic, advocating progress towards rejuvenation. This is a considerable change in comparison to the state of the field even as recently as fifteen years ago, a time when researchers largely kept silent for fear of losing grants and the opportunity for career advancement.

“Targeting signs of aging”. It sounds more like a punch-line of a TV commercial, than a consequence of fundamental science. But as we observed recently, it might actually be possible to achieve just that, using a prospectively designed FOXO4p53 interfering peptide that targets so-called “senescent” cells. More research is needed to fully assess its true translational potential and whether it is even safe to remove such cells. However, these findings pose a very attractive starting point to develop ways to live out our final years in better health.

Aging has often been considered as an integral part of life; a form of “noise” that cannot be targeted or tampered with. This is in part because for long the underlying causes of organismal aging were simply too elusive to comprehend, let alone modify. The chronic build-up of DNA damage has now evidently been established as a major cause for aging, but to counteract the genomic damage that has occurred over a lifetime is an entirely different challenge altogether. One approach to overcome this issue, is to eliminate those cells that are too damaged to faithfully perform their duty and to replace them by fresh and healthy counterparts. Senescent cells are exciting candidates for such an approach.

Comparable to formation of rust on old equipment, like a bicycle, senescent cells accumulate during aging and especially at sites of pathology. They develop a chronic secretory profile that is thought to impair tissue renewal and contribute to disease development, for instance by keeping neighboring cells “locked” in a permanent state of stemness. Senescence can be beneficial in a transient setting, but the genetic removal of senescent cells over a prolonged period of time was found to be safe and to potently extend health- and lifespan of naturally aging mice. Thus, senescence is an established cause for aging and targeting senescent cells is warranted. But can they also be eliminated therapeutically? And are such methods then safe on their own? And last, but not least, would such methods be applicable to not merely delay, but also to reverse aging?

Aging is still inevitable. But perhaps it can be strongly postponed, or even reversed, when independent anti-aging therapies are combined? It remains to be determined whether extension of lifespan is possible in humans, let alone whether this is desirable and then to what age? After all, life could at some point not simply “complete”? While this might be true for some, nobody likes being sick and frail. Imagine the possibilities if we would be able to enjoy our time with loved ones, exercise and travel more and simply just enjoy life in good health, instead of spending it in a retirement home.

Extending the healthy years of life is now closer than ever, but we are still not there yet. While mechanics can
remove defective parts from an old bicycle, it is far more challenging to remove damaged parts from an old body. Anti-aging strategies have therefore necessarily focused thus far on stalling the inevitable for as long as possible by eating less and exercising more. A multitude of new diets make it to the mainstream public each year, but ironically, people tend to exercise less and gain more and more weight. This argues that instead of focusing so much on dietary interventions, independent approaches deserve to be investigated. Here, we underscored the potential of therapeutic elimination of senescent cells, for instance by FOXO4-DRI. In addition, exciting developments were recently reported in the field of stem cell biology, where it was shown that transient expression of the Yamanaka stem cell factors can promote tissue rejuvenation. This is not yet therapeutically applicable, but most likely this will only be a matter of time.

It is no longer merely science-fiction to restore healthspan with rationally designed approaches. To fully achieve the best possible outcome, it will therefore deserve special consideration to combine existing methods to delay aging with the recently developed therapies that counter senescence and promote tissue rejuvenation. With these, we finally have exciting tools to maintain and repair the aging cycle of life. Time to gear up and head for the finish!




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