Geroscience

Introduction

From the biologic perspective, aging is a rather complex term to define. Aging is not a disease but, because aging is the main risk factor for so many chronic diseases and conditions, it is difficult to separate the two operationally. Richard Miller of the University of Michigan defines aging as the “process that progressively converts physiologically and cognitively fit healthy adults into less fit individuals with increasing vulnerability to injury, illness and death,” and this seems like an adequate attempt. It separates aging from the associated chronic diseases (a domain best covered by geriatricians), but it also sets the stage for a recently blossoming new field linking the two areas, termed geroscience ( http://en.wikipedia.org/wiki/Geroscience ).

A “cure” for aging—a fountain of youth—has been a dream of humanity throughout history. And, although aging is inevitable, it is easy to accept that humans age at different rates, so not all 70-year-olds are similar to each other in terms of health. It is also easily acknowledged that life span and health span can be extended simply by adopting moderate changes in lifestyle, including diet and exercise. Unfortunately, this is not easy for most people. Indeed, although public policy has managed to change most people's behaviors in some domains (seatbelts, smoking, and putting babies on their backs represent successful recent examples), reversing behaviors concerning unhealthful habits in terms of diet and exercise is considerably more difficult. For example, it is known that in many laboratory animals, substantially reducing caloric intake extends life span and improves health in old age. Yet, very few people would have the willpower to subject themselves to the harshness of that regimen, and the entire area of dietary restriction (DR) is more suitable for experimental investigations than would be useful as a practical approach to human health.

There is a significant urgency in our need to address the issues posed by the increasing number of older people in the world, including both developed and developing countries. The most dramatic rise in the population is in those 85 years of age and older, including centenarians, and this poses challenges that as a species, we are not equipped to handle. In fact, in addition to the biology, our health care systems, economy, and the very fabric of society will be put to a test to absorb and handle this unprecedented increase in the proportion of older adults in the human population. In addition to the obvious need for more properly trained geriatricians and social workers, there is also a need to understand the biology driving the aging process better as a way to diminish the ravages of old age.

Research on aging biology has exploded in the last few decades, from a relatively backward field focused on descriptive work that catalogued the many changes that occur during aging—first to a highly mechanistic phase driven by genetics, molecular, and cellular studies, and now to the current stage where, without neglecting the still unfinished mechanistic and discovery work, some of the findings are poised for possible application in humans. Interestingly, although there is a pervasive notion that aging is bad, and therefore all changes observed with aging should be reversed, research has shown that this is not really the case. This is because some age-related changes actually represent adaptive positive responses from an organism that by being alive, must strive to maintain homeostasis in the face of multiple challenges. So, although some age-related phenomena appear to be involved in increasing the risk for age-related disease (e.g., the decrease in proteostasis leading to neurodegenerative diseases), others are neutral (e.g., cosmetic changes like hair loss), and some appear to be beneficial to the health of the organism. Attempts to reverse them might have unexpectedly serious consequences (e.g., changes in some hormones, possibly in testosterone or insulin-like growth factor [IGF]). Other changes are the result of pathology and are therefore independent of the aging process per se, yet they are difficult to separate in the case of highly prevalent diseases and conditions.

The main initial drivers of research into the biology of aging included caloric restriction, cell senescence, and the free radical hypothesis. These are still active areas of research, but some of these have undergone significant rethinking. On the other hand, it is generally acknowledged that the main transformative research leading to the current status of the field was the genetic work initially encouraged by the National Institute on Aging (NIA) Longevity Assurance Genes Initiative (LAG). At present, there are several hundred genes that when modified, can increase the life span in animal models. Many of these fall into well-defined (and well-studied) pathways, but many remain orphans and are poorly studied or understood. Interestingly, in some cases, variant alleles of these same genes have been associated with extended longevity in human centenarian studies. Although there is wide recognition of the partially inheritable nature of longevity, the finding that individual genes, when manipulated, could lead to dramatic increases in longevity was not expected and was initially greeted with skepticism. Nevertheless, the finding of molecular drivers of the process brought aging biology research into the mainstream and has resulted in the current renaissance of the field. These events have been reviewed previously and will not be repeated here. Rather, in this chapter I will focus on the following: (1) the main current areas of research; (2) a discussion of geroscience and the importance of studying aging at the most basic biologic level; and (3) a look into future prospects and needs, based on the current status of the field.

The Main Pillars of Research on Aging Biology

In October 2013, a group of experts convened in Bethesda, Maryland, to discuss the current status of research in geroscience, the intersection between basic aging research and chronic diseases. Seven major areas were discussed, and these overlap significantly with the areas identified by López-Otín and colleagues in a recent opinion piece. These represent apparent drivers of the process and will be the focus of this discussion. It should be mentioned, however, that we are still in dire need of markers that can be used for research purposes, independently of whether they are drivers or not. The field has traditionally shied away from looking at biomarkers under the assumption that markers of aging might be too elusive. However, new techniques, including a large set of -omics technologies, now open new possibilities that need to be explored; in the absence of such markers, progress in the field remains hindered. In addition to markers that can be used to test the effects of interventions, there is a need to define mechanistic drivers that can be targeted for these interventions, thus paving the way for possible therapeutics that might delay aging and concomitantly delay the onset and/or severity of multiple chronic diseases and conditions that affect primarily the older population. Major areas currently considered as potential drivers of the aging process include inflammation, responsiveness to stress, epigenetics, metabolism, macromolecular damage, proteostasis, and stem cells. A brief overview of each of these topics follows.