Summary: Geroscientists aim to increase lifespan in humans. This report provides a glimpse into the future of a revolutionary scientific field called geroscience that seeks to slow down the chronic diseases of aging to increase lifespan and health span. Part 4 of a 4-part essay titled Geroscience by Felipe Sierra. [With an introduction by Brady Hartman. ]
Scientists in the geroscience field aim to slow down the chronic diseases of aging and increase lifespan in humans.
In fact, they’ve already done it in lab animals.
This article is the conclusion of the essay Geroscience by Felipe Sierra, Ph.D. In this 4th of 4 segments, titled ‘A Tentative Look Into the Future,’ Dr. Sierra questions the tenets and theories of aging; suggests that the aging process can be slowed or even reversed in some tissues to increase lifespan, and gives us a glimpse into the future of the lifespan-extension field.
Felipe Sierra, Ph.D. is leading the U.S. government’s geroscience research efforts, a group of scientists who are looking into why we age, and how to slow the process down to increase lifespan and reduce the chronic diseases of aging. Sierra is the Director of the Division of Aging Biology at the National Institute on Aging (NIA), a group of researchers specializing in the field of geroscience. The emerging field of geroscience is populated by experts called geroscientists, a type of researcher who aims to understand aging to develop treatments that slow or reverse the aging process to increase lifespan and health span.
A Tentative Look Into the Future
[from the article Geroscience by Felipe Sierra, Ph.D.]
Based on the discussion in this chapter, it is clear that aging biology and geroscience are likely to become important areas of focus in biomedicine in the future. Although impressive scientific advances in the twentieth century have allowed the virtual obliteration of many infectious diseases, as well as significant advances in the detection, prevention, and treatment of many chronic and complex disorders, further advances in the coordinated attack on comorbidities of older adults remain a challenge. Furthermore, it is precisely those gains attained by biomedicine in the last century that are now allowing people to routinely live into their 80s and beyond, but with that apparent success comes the inevitable increase in chronic diseases and disabilities. Now is the time to work toward removing the word inevitable from that sentence. The advances in our understanding of the biology of aging, although still incomplete, give us a powerful tool in this regard. There is no time to lose; societal and health care systems are currently at or near their breaking point, and continuing the current trends will no longer be affordable.
There is therefore an urgent need to develop translational pathways that will allow the goals of aging biology and geroscience to be applied to the rapidly expanding older population. However, many hurdles remain and need to be addressed. Before discussing these, a review of prominent areas in which recent advances have been made will be presented (some have already been discussed in other contexts).
Questioning of Theories and Tenets of Aging
Some of the oldest theories and tenets of aging are currently being questioned, based on new empirical data. The free radical theory of aging has been a stalwart of aging biology research since the mid-1950s.  However, studies have shown that in most cases [45,54] (except as described by Schriner and associates ), genetic manipulation of free radical scavengers and their attendant damage to macromolecules has no effect on life span in mice, at least under the pristine environmental conditions in the laboratory. Another important tenet of aging biology research is the diet restriction paradigm. Diet restriction has been shown to increase life span and health span in many species. [43,113] However, studies in mice, [114,115] yeast,  and perhaps primates [117,118] have suggested that the efficacy of diet restriction is highly dependent on the genetic background of the individual, casting a shadow on our efforts to apply the paradigm (or interventions based on it) to very genetically heterogeneous humans. It should be noted, however, that these caveats are based solely on measurements of life span, but in the free radical and diet restriction paradigms, interventions do seem to improve health span, even when life span is not affected. Because health span is more desirable than merely life span, it would be irresponsible to ignore these areas of research as possibly being irrelevant within the context of aging research.
Interventions to Increase Life Span, Health Span, or Both
Several interventions have been shown to increase life span, health span, or both in several organisms. During the last decade, there has been a veritable explosion in the number of interventions purported to increase life span in mice and other species. Although much of the research has been based on genetic manipulations, these studies have pointed the way toward druggable targets. The best publicized of the pharmacologic interventions have been rapamycin and resveratrol, both of which extend life span and health span in a variety of organisms. Much controversy has focused on the fact that resveratrol only increases life span in mice subjected to metabolic stress.  In addition to the obvious fact that many people are under metabolic stress, these misgivings must be tempered based on two observations from the studies: (1) resveratrol improves health span, even in mice that do not benefit in terms of life span; and (2) resveratrol must be regarded as a first-generation drug, and second-generation sirtuin activators (STACs) have shown improvement of life span in mice under normal diets.
A second line of research is based on cellular (rather than molecular) aspects of aging. In the last decade, it has been found that senescent cells accumulate in various tissues and organs during aging to a larger extent than previously believed. [119-121] In addition, Campisi and coworkers have shown that senescent cells secrete many bioactive molecules, primarily proinflammatory and matrix-modifying factors, which can disrupt their immediate tissue vicinity, or perhaps even contribute to the organism-wide chronic inflammation of older adults. [101,122,123] Most importantly, using an elegant genetic trick, it has been recently shown directly that removing senescent cells leads to significant improvements in function in several systems, including adipose tissue, skeletal muscle, and the eye.  This is in spite of the fact that like resveratrol, the intervention did not lead to increased survival. Importantly, late life clearance of senescent cells attenuated the progression of already established age-related disorders and improved physiologic function (see next section).
Age-Related Pathology: Preventable and Perhaps Reversible
At least in some cases, age-related pathology is not only preventable, but might be reversible. As noted, removal of senescent cells leads to a reversal of already clinically observable pathology in several tissues.  In addition, there has been considerable recent excitement about the use of heterochronic parabiosis as a model to provide evidence for the existence of factors in the circulation of a young mouse that can reverse the aging phenotypes of an old mouse. [85,87-90] Parabiosis is a surgical technique to produce anastomosis and thus a sharing of circulatory systems between two individuals. This innovation has been to introduce heterochronism, in which the two animals differ primarily in their age. Using this system, laboratory studies have provided the first direct demonstration that a factor in the circulation of the young mouse (later identified as an activator of the notch-delta pathway) was capable of activating stem cells in old muscle. [85,125] More recently, others have been able to identify GDF-11, a member of the transforming growth factor (TGF) family, as a factor that can reverse already existing age-related cardiac hypertrophy in older mice.  GDF-11 also reverses aging phenotypes in several additional tissues, including the brain. [88-90]
These and many other pieces of data give credence to the belief that aging biology is poised to produce major breakthroughs in the way chronic diseases of older adults are viewed, both in the laboratory and in the clinic. However, many additional developments are needed before this promise can be brought to fruition. Without neglecting the need for continuous further discoveries in the areas of basic and preclinical translational research (see later), there are other major roadblocks beyond basic biology that will need to be addressed. First, potential interventions will need to be tested extensively for safety and pharmacokinetics in aged animal models before testing effects on multiple comorbidities in human clinical trials. This is particularly important because the interventions identified through research on the basic biology of aging are likely to have widespread effects on many organs and systems, and to be administered for extremely long periods, so there will be a need for very extensive analysis of these issues globally and longitudinally. Some of this work can be started already in those cases (e.g., with metformin, rapamycin, resveratrol) in which phase I or II clinical trials are already in progress for specific diseases or conditions. Ancillary additions to these studies to determine possible effects on diseases and conditions not primarily targeted would provide a fiscally conservative and effective means of obtaining preliminary information in this regard. In further studies, better-defined outcome measures need to be developed and validated.
A related roadblock is represented by the current status of clinical trial paradigms. The current model for clinical trials typically excludes subjects with morbidities unrelated to the one under study, as well as (more often than not) older adults.  However, these are exactly the populations being targeted for post-trial clinical purposes, older adults with multiple comorbidities. New paradigms will need to be developed to study the effectiveness of potential interventions in older animals and humans with multiple comorbidities. In animals, this involves testing interventions in aged animal models of the various diseases, preferably those that develop the disease naturally, rather than artificially through genetic manipulation. In the clinic, it will require a dramatic conceptual change to allow that although testing under the current sanitized conditions might allow for faster, cheaper, and cleaner analysis of the data, the onus is on trying to translate the findings into the real world—that is, the intervention needs to be effective in the clinic, rather than simply efficacious under tightly controlled conditions (refer to http:// www.policymed.com/2014/02/fda-policies-and-procedures-for-proposed-trial-design-aimed-at-multiple-chronic-conditions. html#sthash.XqinSUlF.dpuf) [Link to article]. In addition to testing effectiveness in clinically recognized diseases and conditions, many of the interventions currently under investigation might lead to accelerated recovery from clinical perturbations, such as chemotherapy or anesthesia. For example, research on diet restriction has led Raffaghello and Lee and colleagues to propose that a short period of fasting prior to chemotherapy is likely to decrease the notorious side effects of this treatment. [127,128] After encouraging preliminary data in models ranging from yeast to mice,  such hypotheses are currently in phase II clinical trials.
Exciting and promising as the current state of affairs appears, it is important to mention that although much emphasis has been placed on translating findings into clinical practice, scientists are well aware that many crucial developments in medicine have come from basic research that in itself was not meant to be translatable. Some of the findings described were not meant to be translated into humans, and yet clinical trials are being performed or are about to be initiated. Therefore, just as the translation, preclinical, and clinical paradigms need to be strengthened, this needs to be done without sacrificing basic research on the biology of aging. There have been many dreadful graphic depictions of the arduous road from “initial druggable hit” to U.S. Food and Drug Administration (FDA)–approved commercialization of drugs. Much effort has been devoted to strengthening the translation aspect of biomedical research. However, it is important to recognize that at the starting line of that graphic lies the initial discoveries that have come from basic research. If translation comes at the expense of basic research, soon there will be nothing new to translate; it is crucial that the spigot of basic biomedical research be kept open and flowing freely. In the specific area of aging, much more basic research remains to be done on molecular pathways (e.g., on known pathways such as the growth hormone–insulin–IGF-1–FOXO, mTOR, sirtuin, and AMPK [5′-adenosine monophosphate-activated protein kinase] networks and on new ones yet to be discovered), and on cell-based interventions such as stem and senescent cells, both of which show exceptional promise.
Thus, the potential impact of geroscience-based interventions is so broad that in parallel with the biomedical and population health aspects, it will be important to estimate the potential effects on health care and pension systems, as well as distribution of the workforce and other societal aspects. These will not be addressed here, but are no less important.
- Aging is the major risk factor for most chronic diseases and conditions affecting older adults.
- The rate of biologic aging can be manipulated (extended) by a variety of behavioral, genetic, and pharmacologic means in many animal models.
- When the rate of aging is decreased, it is most often accompanied by a delay in and decreased severity of naturally occurring diseases and conditions, as well as improved resistance to laboratory-induced diseases.
- At the molecular and cellular levels, a finite number of factors have been identified that control the rate of aging.
- The rapid pace of new discoveries makes it likely that additional pathways and drugs will be defined in the near future, thus making it likely that clinically relevant advances will occur as a result of studies on the biology of aging.
- A new field, geroscience, intends to bridge the gap and increase our understanding of the molecular and cellular underpinnings of aging that make it the main risk factor for disease and disability.
– by Felipe Sierra, Ph.D. [Editor’s note: this article continues in earlier sections.]
Previous Sections of the Geroscience Article
- Part 1 of 4: Introduction to the Geroscience essay, and backgrounder on Dr. Sierra.
- Part 2 of 4: The Main Pillars of Research on Aging Biology (the main areas of lifespan-extension research).
- Part 3 of 4: Geroscience (explains the goals of the field that aims to increase life span).
- Part 4 of 4: A Tentative Look into the Future (this article on ways to increase life span).
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References Accompanying this Section
(References provided by Dr. Felipe Sierra, accompanying the essay Geroscience.)
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Cover photo credit: Getty Images / Davizro.
National Institute on Aging. “Felipe Sierra.” National Institutes of Health. Web, Retrieved 10 Jan 2018. Link to Article.
Felipe Sierra. “Geroscience.” Brocklehurst’s Textbook of Geriatric Medicine and Gerontology, 8th Edition, Authors: Howard Fillit Kenneth Rockwood John B Young. ISBN: 978-0-7020-6185-1. Link to book.
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