The Geroscience Perspective

The authors of this article express a representative version of the geroscience perspective on aging research and its application in medicine. It is similar to that of the Longevity Dividend initiative of the past decade, which is to say that if a large amount of time and funding is invested, perhaps calorie restriction mimetic and similar marginally effective drugs can be brought to the clinic in order to modestly slow the progression of aging and add a few years of healthy life expectancy sometime prior to 2030. I believe I'm not the only one to be entirely underwhelmed by this strategy. This is not the future of aging research that we should either want or support.

Yes, it is a good thing that a sizable fraction of the research community is now prepared to work towards treating aging as a medical condition, and to advocate for that work in public. It wasn't always this way, and it took considerable effort to bring about the present renaissance. Yet if the research community aims low, consuming funding and careers to make progress towards goals for human longevity that are only a tiny bit removed from doing nothing at all, what is the point? If we want to instead see meaningful progress towards rejuvenation therapies capable of achieving a far greater impact on aging and the health of older people, we should look to groups like the SENS Research Foundation and its allies in the research community, or the companies developing senolytic therapies to clear senescent cells. The goal should be to repair the causes of aging, aiming to put a stop to aging, to bring it under control, not merely slow it down a little.

Over the past decades, the compression of morbidity was a basic strategy in gerontology. This strategy is aimed at limiting morbidity to a short time period near the end of life, thereby reducing the burden of diseases and disabilities through delay in the age at onset of the most common aging-related pathological conditions. A few years ago, a new direction in geriatric medicine, geroscience, began to develop. This interdisciplinary field of research is aimed at understanding the mechanistic links between aging and aging-associated diseases and centered primarily on extension of healthspan. According to the "geroscience hypothesis", aging could be manipulated in such a way that will in parallel allow delay the onset of all age-associated chronic disorders, because these pathologies share the same primary underlying risk factor, age.

Healthspan extension is a central component of activities aimed at achievement of 'optimal longevity', a condition defined as 'living long, but with good health and quality of life' including improved productivity, functioning and independence. Currently, the research attempted to enhance healthspan are focused primarily on slowing the biological processes underlying aging such as dysfunctions of mitochondria, impaired proteostasis and stem cell function and maintenance, deregulated sensing of cell energy status and growth pathways, cellular senescence, age-related decrease in stress resistance, as well as oxidative and inflammatory stress. These processes interact, influencing each other in order to maintain the normal pathways of cellular signaling and to support organismal homeostasis. The compensatory mechanisms mediating these processes, however, became exhausted when reaching a certain age and various aging aspects are manifested, enhancing as a consequence the risk of functional declines and progression of age-associated chronic pathologies.

Aging is traditionally regarded as 'natural' and consequently unpreventable process. However, in the opinion of many field experts, the idea that aging is inevitable part of human nature is rather questionable. Indeed, most present-day evolutionary theories postulate that aging has arisen as a by-product of fundamental evolutionary processes and does not have any specific function. If aging is in fact not an inadmissible component of life, then it might be manipulated like other processes that are commonly believed to be pathological or unnatural. The basic supposition underlying anti-aging research is that age-associated senescence may be regarded as a complex of pathophysiological processes that could be prevented, delayed, or even reversed.

The further elaboration of pharmaceuticals (both supplements and clinically approved drugs) specifically targeted at age-related pathologies is one of the most rapidly developing fields in modern biogerontology. An important point is, however, that most substances with potential anti-aging properties are apparently multifunctional and targeted at various molecular pathways that mediate aging. Furthermore, there is only limited evidence to demonstrate overall health benefits of using such substances so far. Findings from epidemiological studies reporting the long-term health impacts of these agents are rather inconsistent.

Another reasonable approach in anti-aging pharmacology is evaluation of the geroprotective potential of medications already approved by regulatory authorities for treating various pathological conditions related to aging. Among them, metformin, statins, beta-blockers, thiazolidinediones, newer generation β-adrenergic receptor inhibitors, renin-angiotensin-aldosterone system inhibitors, as well as anti-inflammatory medications appear to be the most promising drug candidates in this respect. The safety of these drugs has been confirmed in a number of clinical trials. This is also compelling evidence that they may improve health, well-being and physiological functioning in elderly patients suffering from chronic pathologies. One problem is that these substances are not used currently for treating age-related pathological conditions in the absence of clinical manifestations of particular illness. There are, however, good reasons to suggest that these agents could theoretically be redirected to preventing or treating other syndromes or conditions commonly associated with aging.

Despite an extraordinary rapid technological progress in pharmacology, there are few new preparations in the development pipeline now. Thereby, drugs generated on the basis of new knowledge gained from biogerontological research that can delay or prevent most age-associated disorders would apparently become "blockbusters" of modern pharmaceutical industry and market. That follows the idea that the extension of the healthy life expectancy by slowing aging process is the most efficient way to combat aging-related chronic illnesses and disabling conditions representing serious medical, social and economic issue in modern societies. This idea is referred to as the "longevity dividend" in the contemporary literature. Discovery and development of anti-aging drugs could likely provide an opportunity for revitalization of the drug development pipeline. Indeed, if it would be possible to slow down the aging process per se, then that would allow delay or prevent most aging-related disorders rather than combating them one by one, which is the conventional approach in the present-day disease-based paradigm of drug development.



Instead of their current direction we should focus on the positive.
As I said before, neither the public opinion, nor the opinion of the medical research community is easily swayed.

The one way to do it is to show them results and that is currently impossible because funding is hard to come by. Even in this article they mention senolytics, so obviously they cannot deny results ones they have been presented.

In a world where aging is considered a viable target for intervention researchers can get the funds they need for rejuvenation therapies and do the research and present the results.
At the end of the day this is opening the floodgate. Yes they will not jump on rejuvenation whether it's SENS or some other idea and make it their only target of research, but if SENS and the few other aging research foundations popping up now can actually fund their research with government grants - this will change the field completely.

Also, it's good to point out that third parties will take notice of this validation that indeed aging is targetable and even if government grants are still hard to come by, then at least a financial involvement by the public is much more probable - which in my view will always remain our true moving force.
Philanthropy goes so far. Business on the other hand is an endless pool of opportunity.

Also Steve is right. Radical messaging is not the way - instead we should definitely be clear that we want to do better than what the mainstream is doing - no need to mention our ultimate goal - and if we're lucky we could get the money to the right people and prove that we can indeed do better.
Then they won't be able to deny it and just like senolytics they will be pressed to accept the results. This is the way to go. For now.

Posted by: Anonymoose at July 25th, 2017 8:18 AM

@Anonymoose thanks, although I wish to say that ultra conservative messaging also isnt the way either so there must be a middle road that strikes a good balance. Geroscience actually supports LEAF and promotes our articles so they are helping on some level even if they are more conservative in approach.

I also find the idea of slowing aging down somewhat amusing, it is likely to be far harder to slow aging down than actually repair the damage. I see little value in CR mimetics and am interested in developing biomarkers and repair therapies as the way forward.

Posted by: Steve Hill at July 25th, 2017 8:28 AM

I think we should be more positive - even Geroscience is now fully behind treating aging directly as the most efficient way to prevent the diseases of aging, and actually the stated targets of mitochondrial dysfunction, impaired proteostasis, stem cell function, deregulated energy sensing, cellular senescence, etc., etc., (probably influenced by the Hallmarks of Aging paper) overlap with SENS quite nicely.

It just remains for SENS to demonstrate a damage removal rather than metabolic tinkering is a more effective approach.

Posted by: Mark at July 25th, 2017 8:55 AM

@Mark Geroscience follows the Hallmarks of aging and they did an article about it earlier this year so they are definately thinking repair based approaches. LEAF also supports the Hallmarks model of aging as well as SENS because the two are essentially the same thing as Aubrey has eluded to on a number of occassions.

Posted by: Steve Hill at July 25th, 2017 9:04 AM

Saying we can do better than rapalogs and elucidating why with science rather than with feeling IS the middle ground.

No single therapy will increase the lifespan of a mouse significantly, we already know that.
So here is where the focus on health will help rather than impede.

It's a blessing in disguise really.

Posted by: Anonymoose at July 25th, 2017 9:08 AM
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