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 FOXO4-p53 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!

Link: https://doi.org/10.18632/oncotarget.18046

Comments

"However, these findings pose a very attractive starting point to develop ways to live out our final years in better health."

What? Compression of morbidity again?

"It remains to be determined whether extension of lifespan is possible in humans, let alone whether this is desirable and then to what age?"

Great, medical researchers discussing when they should stop curing people and let them die...

Anyway, the change to talking openly about curing aging is an improvement.

Posted by: Antonio at June 8th, 2017 10:13 AM

Antonio,

"It remains to be determined whether extension of lifespan is possible in humans, let alone whether this is desirable and then to what age?"

I don't think this part should be surprising to you. Seemingly every discussion about it brings that up. And a lot of the time it's "well, I don't want it, so I don't think anyone else should have it" kinds of arguments. Or how you're immoral or unethical for wanting to live longer. I'm not much of a fan of someone else deciding how long everyone else can live, but that scenario would not shock me in the slightest. I would not be surprised at all if there were attempts to legislate maximum life span at some point.

Posted by: Ham at June 8th, 2017 10:56 AM

Any "press" is good "press", no?
It's good mainstream researchers are talking about it.

Posted by: Anonymoose at June 8th, 2017 10:59 AM

" I would not be surprised at all if there were attempts to legislate maximum life span at some point."
Fastest road to inequity.

Posted by: Anonymoose at June 8th, 2017 11:07 AM

Anonymoose,

Perhaps. But I'm sure their argument for that could be spun as a "good" to prevent overpopulation, generational turnover, new ideas, etc, etc. I don't think something like that is necessarily likely, it just wouldn't surprise me. After all, too many people like to tell everyone else how to live their life.

Posted by: Ham at June 8th, 2017 11:22 AM

Very encouraging!

June 16 is another big day. I'll be looking closely to see if the FDA allows the TAME trial to go ahead. SENS is still our best option to reverse the horrors of aging, however, any movement of the needle will break the 'spell' humanity has been under regarding aging. Once people know it can be modified and altered, everything will change and we will see multi-approach attacks on aging. Well, that's my hope anyway.

Posted by: mborbely at June 8th, 2017 11:31 AM

"It remains to be determined whether extension of lifespan is possible in humans, let alone whether this is desirable and then to what age?"

If that question comes up in a discussion I do the Liz Parrish maneuver and point out that 100 years ago 99% of people died naturally from infectious diseases, 1/3 of them below the age of 10. Before that they died of famines and before that they were eaten by predators. So we're already far into extension of human lifespan, only our technology improves.

A rethoric teacher once told me that someone who argues against stuff he does himself is either a liar or a hypocrite. He may choose himself, but in any case he lost the moral high ground.

Posted by: Matthias F at June 8th, 2017 11:52 AM

"He may choose himself, but in any case he lost the moral high ground."
If forcing people to die was ever in a morally coherent position to take, let alone a high one.

Posted by: Anonymoose at June 8th, 2017 11:56 AM

@Anonymoose

You're right, but often these people fight for a place for their kids. So you have to bring their kids into the equation. Btw: By their thinking they're not forcing anyone.

Posted by: Matthias F at June 8th, 2017 12:12 PM

Actually, not their kids, but some non-existent kids that will be born some decades or centuries in the future.

Posted by: Antonio at June 8th, 2017 12:27 PM

Basically, they want to take away the rights from real people (specifically, the right to life) in favor of the alleged rights of imaginary people.

And no, I'm not talking about ISIS...

Posted by: Antonio at June 8th, 2017 12:35 PM

And don't forget that "Rust remover" also has toxic side effects to your bicycle unlike a WD-40-like dietary intervention.

Posted by: Armstrong at June 9th, 2017 8:06 AM

@Armstrong
Would be a valid point if the toxic "side effect" wasn't a purposefully looked for reaction. Senescent clearing therapies work through targeted cytotoxicity. Your own body has many such mechanisms - if it didn't, it would be incapable of fighting off infections for instance.

Posted by: Anonymoose at June 9th, 2017 9:34 AM

Interesting that they highlight the ability of senescent cells to cause proliferation of surrounding cells through 'stemness' (to replace those cells that are senescent, and which are also signaling to the immune system that they should be killed). Really brings home how important SASP is when applied acutely rather than chronically.

For me this is starting to fill in the blanks between senescent cell accumulation, stem cell exhaustion and immune system dysfunction, and gives me renewed hope that these three areas will combine to give us the first real, effective rejuvenation therapies for humans in the not too distant future.

As for the so called ethical issues, I find it encouraging to see new groups thinking their way through issues we have long been familiar with, and slowly but surely moving towards our position - namely that rejuvenation therapies are an unalloyed good for the world.

Posted by: Mark at June 12th, 2017 5:21 AM

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.