Fight Aging!

The firm distinction made between aging and age-related disease is a modern phenomenon, a product of the way in which the regulation of medical research and development has progressed. It wasn't so very long ago, considered in the grand scheme of things, that much of dementia and cardiovascular disease were thought parts of aging, prior to the ability to accurately map and categorize specific biological manifestations of aging. Present regulatory systems are set up to approve (a) the existence of clearly defined and bounded medical conditions based more on their biochemistry than their epidemiology, and (b) treatments narrowly applied to one approved condition. The result is a slow slicing of aging into a potentially endless series of named conditions, as each small piece of the enormously complex end state of decline is defined and given a name. This implicitly favors the poor strategy of trying to control narrow parts of the complicated end stage of disease, pretending they are isolated when in fact they are not, and makes it harder to pursue the much better strategies of either prevention or ways to repair and reverse the root causes of aging.

Aging and age-related disease are clearly not distinct from one another. Aging is just a collection of countless age-related diseases, the few defined and the many not yet defined. Age-related diseases are just arbitrary lines drawn around parts of aging. Looking at it a different way, an age-related disease is an aspect of aging that has progressed far enough to be unbearable. Aging and age-related disease are caused by the same underlying mechanisms - the cell and tissue damage outlined in the SENS research proposals.

Is aging as a whole a disease? Can we just draw a line around the whole thing? This question has been asked ever more frequently of late. It is trivial semantics - except that regulators will not let a treatment for aging progress to the clinic unless they agree that aging is a disease by their formal definitions. Which they currently do not. Absent a defined path to the clinic, research funding for efforts to treat aging as a medical condition is much harder to obtain than would otherwise be the case. The whole development pipeline suffers, all the way back to fundamental science in this part of the field. It has required philanthropy and advocacy and non-profit organizations dedicated to aging to make any meaningful progress since the turn of the century. Now that it is becoming plausible to effectively reverse some of the causes of aging, such as via senolytic therapies to destroy senescent cells, it becomes ever more important that this ridiculous situation is resolved in a way that allows funding to flow and therapies to reach the clinic.

The Continuum of Aging and Age-Related Diseases: Common Mechanisms but Different Rates

The longstanding question if old age is itself a disease has been addressed since ancient times, starting from the Roman playwright Terentius, who claimed "senectus ipsa est morbus" (old age itself is a disease), and Cicero who some decades later argued in De Senectute: "pugnandum, tamquam contra morbum sic contra senectutem" (we have to fight against aging, as we do against a disease). These quotations elegantly summarize a long-held view of aging and old age addressed by several scholars. Notwithstanding, with the birth of modern medicine in the nineteenth century, this old tenet has been somehow put apart, as the main interest at that time was to define precise medical entities (diseases and syndromes) and their causes (infections, genetics, degenerative processes, inflammation, etc.). This process ended up in considering aging and diseases as separate phenomena that could eventually interact but that are essentially different in nature.

In this review, we will reappraise and challenge the old tenet that aging and age-related diseases (ARDs) and geriatric syndromes (GSs) are separate entities, and we will suggest instead that both should be considered as parts of a continuum. To support this hypothesis, we will highlight that aging and ARDs/GSs share the same basic molecular and cellular mechanisms. Aging is the predominant risk factor for most diseases and conditions that limit healthspan. Accordingly, interventions in animal models that end up in an extension of lifespan prevent or delay many chronic diseases. Why? For many years the explanation was that aging per se is a physiological condition, which favors the onset of many diseases. However, their relationship is likely much more complex, and a major reason is because they share the basic mechanisms. Assuming that aging and ARDs/GSs share the same mechanisms, which are commonalities and differences?

We will argue that an integrated hypothesis, fitting most epidemiological and experimental data, is to consider ARDs/GSs as an acceleration of the aging process. The conceptualization of accelerated aging started from the observation of rare genetic disorders such as Hutchinson-Gilford progeria. Here, we extend the concept of acceleration of aging to those members of the general population undergoing ARDs and GSs, in comparison with a small minority of people, such as centenarians, who reach extreme age largely avoiding or postponing most ARDs/GSs. This consideration is reinforced by the observation that among centenarians there are few subjects who never suffered of any overt ARDs. These exceptional individuals can be taken as a proof of principle that "healthy" aging and diseases can occur separately, as phenotypes at the extreme of a continuum, which is fueled by a common set of molecular and cellular mechanisms.

Which are the basic mechanisms shared by aging and ARDs/GSs? A group of international experts identified "seven pillars" which actually include adaptation to stress, loss of proteostasis, stem cell exhaustion, metabolism derangement, macromolecular damage, epigenetic modifications, and inflammation. Following this idea, the very difference between aging and diseases would relay on the speed and intensity of aging cellular and molecular processes, combined with the genetic and lifestyle predisposition of specific organs and systems. Thus, on the long run, all the functional domains undergo a physiological decline that eventually can lead to overt clinical diseases, favored by system-specific genetic and environmental factors. This progressive path generates a continuum between the healthy juvenile status and the impaired unhealthy elderly one. Accordingly, all major ARDs/GSs are characterized by a long subclinical incubation period, where the diagnostic signs of diseases are largely unobservable due to the high operational redundancy of biological systems.

In conclusion, a debate exists on whether aging is a disease in itself. Some authors suggest that physiological aging (or senescence) is not really distinguishable from pathology, while others argue that aging is different from age-related diseases and other pathologies. It is interesting to stress that the answer to this question has important theoretical and practical consequences, taking into account that various strategies capable of setting back the aging clock are emerging. The most relevant consequence is that, if we agree that aging is equal to disease, all human beings have to be considered as patients to be treated, being an open question when this treatment should start. Many mechanisms proposed to cause aging are the same as those known to underlie ARDs/GSs, lending support to the hypothesis that the aging phenotype and ARDs/GSs are not separate entities but rather the visible consequences of the same processes which likely proceed at different rates.

A second conclusion is that medicine should combat aging to combat many ARDs at a time and not one by one. In this perspective, one could envisage following two possible strategies to attain this result: (A) Try to slow the aging rate through changes in life style, and possibly drugs or medical treatments that counteract the impairment of mechanisms such as those proposed in the "seven pillars." This strategy should help people to stay healthy and active as long as possible and pospone ARDs for decades, ideally until the apparently inevitable limit of human lifespan. (B) More radically, try to rejuvenate human tissues, organs, and whole body. In this case, also the limits of human lifespan could be likely overtaken.

We are relatively ready to the first strategy that appears more feasible and acceptable from an ethical and social point of view, as it would be very similar to what is already happening nowadays, i.e., an increase in life expectancy and in the number of people who attain 90 or 100 years of age and more in good health. We are not yet ready, in particular from a social and ethical point of view, for the second strategy, which opens uncanny scenarios of rejuvenating bodies and very long life for the bulk of the population, a topic addressed in utopian, dystopian, and science fiction novels. Taking into account the fantastic, unprecedented rate of scientific discoveries in the field of aging and rejuvenation, it is timely and urgent to open a large debate.