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Can the Top-Down Institutional Approach Promote the Right Sort of Research and Development to Treat Aging?

Most scientists who spend their professional lives within large institutions, such as the big universities, the National Institute on Aging (NIA), and so forth, tend to favor institutional solutions. In practice that means slow engineering of change within the established hierarchy, rather than stepping outside it, or where a new need is identified, meeting it with the creation of a new institutional edifice much like those that already exist. This is the top down approach to development: structure and delegation, provide big-picture guidance and leave the details up to lower levels of the hierarchy. It is advocated in a recent open access position paper authored by a noted Russian researcher, one of those who led the development of plastinquinone based mitochondrially targeted antioxidants as a potential means to slow the progression of aging.

It is necessary to establish an International Agency for Research on Aging

Extending healthy lifespan is one of the main goals of gerontology and preventive medicine. There are potential interventions which might delay and/or prevent the onsets of many chronic pathologies associated with human aging. The affected pathways have been identiļ¬ed, and the behavioral, dietary, and pharmacologic approaches to preventing and treating age-related disorders have emerged. Interventions that target the aging process in its entirety appear to be more effective in preventing a broad range of age-related pathologies than specific interventions targeting such pathologies. Development of the new anti-aging drugs opens broad prospects for the pharmaceutical and healthcare industries. However, if human longevity continues to advance, the incidences of age-associated diseases, including cardiovascular diseases, type 2 diabetes, and cancer would also increase thus presenting a tremendous challenge for humankind. The search for adequate models for selecting the effective and safe methods of healthy life extension has become a priority in biology of aging.

There are at least two broadly accepted definitions of pharmacological compounds capable of intervening in aging: a) anti-aging drugs, which presumably reverse the aging process ('rejuvenation'), and b) geroprotectors, which are supposed to prevent premature aging and/or slow down or postpone aging. The term "longevity therapeutics" has been introduced for drugs that can interfere with the process of aging and extend the mean and/or maximum lifespan, preserve physiological functions and mitigate the onset and severity of a broad spectrum of age-associated diseases in mammals. Potential geroprotective agents have been subdivided into several groups: those that demonstrate an anti-aging effect without any evidence of lifespan increase; those that increase lifespan by reducing the incidence of age-associated pathology; and those that extend lifespan presumably by reversing the aging process itself. Most of the evidence related to these definitions and classifications has been gained in animal studies.

The designs of most such studies were found to have various deficiencies which led to confounding results. Therefore, there is the need to work out standard guidelines for testing such drugs and evaluating their life extending potential as well as various late effects, including tumor development. Guidelines for testing should include such significant elements as animal models, testing regimens, and biomarkers/endpoints. To this end, it is necessary to develop international standards for conducting the preclinical and clinical studies of agents intended to be used in pharmacological interventions in aging, as well as for evaluating the results of such studies. In the years to come, a promising agenda could be the development of new biomarkers based mostly on biochemical and genetic tests for short-term screening of potential agents. Collaborative studies of anti-aging drugs and geroprotectors conducted in various laboratories could be particularly promising.

In 2000, an international program on the assessment of the efficacy and safety of geroprotectors was proposed. It was suggested that the proposed program could be established under the auspices of the United Nations Program on Aging, the World Health Organization, and the International Association of Gerontology and Geriatrics. Unfortunately, the proposed program has not been implemented. We believe that it is worth reverting to that earlier proposal. Whereas the main challenge for healthcare in the 20th century had been the rapid increase in morbidity and mortality from malignant neoplasms, in the 21st century the primary challenge will be the effects of global aging on public and individual health. Therefore, the establishment of an International Agency for Research on Aging (IARA) under the auspices of the World Health Organization, similar to the International Agency for Research on Cancer (IARC), is expedient. Similarly to IARC, the objective of IARA should be the promotion of international collaboration in gerontology and geriatrics.

Can this really work, however? The challenge with large institutions is that the natural human inclination to conservatism, to playing it safe, to avoiding change, is magnified tenfold. If you want to maintain the status quo, that might be great, but if you want to change the world, then institutions are usually the enemy. The NIA mission involves "understanding the nature of aging and the aging process, and diseases and conditions associated with growing older, in order to extend the healthy, active years of life." This organization has been in existence since the 1970s; why are we still aging at much the same pace, with none of the fundamental causes meaningfully addressed? All of this funding has certainly led to the accomplishment of a great deal of scientific work, but sadly next to nothing of practical use when it comes to ways to slow or reverse the aging process. This isn't because they have no starting point: many of the root causes of aging have been well described for decades. Yet there is absolutely no danger that the NIA will meaningfully support the best directions for rejuvenation in the near future.

Much the same is true of other large institutions. They favor examination of aging, small changes to aging achieved by tinkering with metabolism, or the safe old school path of palliative methods of making age-related disease slightly less worse. Few exhibit any interest in the well known potential approaches to reversing aging by repairing its root causes. The World Health Organization won't even acknowledge that aging can be treated at all! What one can expect from a sizable institution charged with a specific mission is for its functionaries to pick the smallest possible set of changes they can aim for, and then work ineffectually to achieve those changes.

Senolytic rejuvenation therapies are being pioneered outside the institutions, as they did not support it despite the decades of evidence. The Methuselah Foundation and SENS Research Foundation, instrumental in steering the research community towards better strategies, were created by outsiders because the institutions of aging research would not acknowledge the need and the opportunity for effective rejuvenation development programs. Revolution and new, useful paths forward near always arise outside the mainstream, and are opposed by establishment institutions for as long as possible. That certainly happened, and is still in the process of happening, for rejuvenation research. So I'd say that the support we give to a better future is best directed to bottom-up approaches. Rebels, revolutionaries, startups, and rejuvenation biotechnology. New ideas, new directions, not the same old careful preservation of the status quo that exists in the largest research bodies.

Comments

Of course the top-down institutional approach to curing aging will not work. In addition to a natural tendency towards conservatism is the tendency towards group-think. Look at all of the other big science stuff and you see things that are not working. NASA has failed to develop the technology to enable large scale space colonization. ITER has no hope of developing affordable commercial fusion. The list goes on and on.

The problem of large-scale institutions, especially public ones, is that they are bureaucracies. Bureaucracy, by definition, does not work (it seems to be rooted in human nature). Bureaucracy is inherently dysfunctional and therefore cannot work. Thus, any political philosophy that is based on the efficacy of bureaucracy cannot work as well.

Posted by: Abelard Lindsey at July 5th, 2018 5:20 PM

"NASA has failed to develop the technology to enable large scale space colonization."

NASA put men on the Moon in less than a decade, and of course it was an institution then also. The problem is not there, but in NASA's change of attitude and values (now the manned program is more like a jobs program than an exploration program).

"ITER has no hope of developing affordable commercial fusion."

Wrong. ITER has been strictly on schedule since the new director general took up his post in March 2015, and it seems very likely that first plasma will be achieved in December 2025 as planned by his team. Again, the problem was not being an institution, but its structure and work style (ITER itself was quite powerless compared to the member states and the result was chaos; now that has changed to a more centralized chain of command and the director has more freedom to use the budget as he sees fit).

Posted by: Antonio at July 5th, 2018 7:13 PM

Reason, what you call "institutional approach" I would call "state approach". After all, the institutions you mention, like NIA and WHO, are state institutions (in the case of WHO, it's formed by states). The trend to conservatism you see in the "institutional" structures (state structures, for me) is derived from the fact that the state is a structure in which, by its nature, everyone is obliged to participate. So, people who is obliged to do something obviously will do it in an inefficient way. I'm not saying the state is unnecessary, but just pointing an intrinsic defect in it. Non-state structures also have potential problems, and this could be discussed as well.

Posted by: Nicolas Chernavsky at July 8th, 2018 8:27 AM

Huh? AFAIK, people that work in the NIA or the WHO are there because they replied to a job offer, were accepted and are paid for their work.

Posted by: Antonio at July 8th, 2018 1:23 PM

Reason, I think you underestimate the value institutions and state institutions. Sure they can be big and ponderous but they have also contributed a great deal to the basic science and knowledge we have. Whilst they are not laser focused on "curing aging", they are still adding value in the background which those working on the solutions can also benefit from.

Posted by: Steve Hill at July 8th, 2018 1:56 PM

The public institutions are there to facilitate economic development as well as to protect the safety and welfare of the public. Unfettered capitalism is a road to economic and safety disaster. Companies only look out for themselves not the safety and welfare of the public if they are not regulated so as not to harm the public.

Posted by: Biotechy Marcks at July 9th, 2018 9:37 AM

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