Healthspan Pharmacology

Introduction

Aging is a complex and multi-factorial process that is not well defined. The majority of evolutionary biologists, like Michael Rose, characterize aging as a decline or loss of adaptation with increasing age, caused by a time-progressive decline of William D. Hamilton's forces of natural selection. ¹ Although there are a number of variants of this definition, we can all agree that as we age, we will experience a progressive accumulation of cellular damage and a degradation of repair and maintenance mechanisms, leading to a gradual deterioration of physiological functions. This process, which is highly conserved across species throughout evolution, creates progressive dysfunction associated with frailty and age-related diseases and eventually leads to the death of the organism.

Over recent decades, improvements in medical diagnostics and procedures, as well as improvements in hygiene, have resulted in a steady increase in human lifespan, ^{2 –10} but this increase has unfortunately been accompanied by ever-growing occurrences of diseases of aging, such as diabetes, neurodegenerative diseases, cancer, and cardiovascular diseases. ¹¹ Therefore, understanding the mechanisms of aging, defining the most important risk factors for the development of chronic diseases of aging, and identifying pharmacological interventions to ameliorate the aging process are more important today than ever. Over the last two decades, using several model systems, such as yeast, fruit flies, worms, and mice, numerous evolutionarily conserved pathways that regulate longevity have been identified, and the modification of these pathways either intrinsically (e.g., genetic modifications for deletion, down-regulation or over-expression) or extrinsically (e.g., environmental factors, use of pharmacological agents) have been shown to extend the lifespan of the model organisms. ^{12 –30}

Most of pharmacological intervention studies have focused on lifespan extension of animals, but very little attention has been given to the aspect of pharmacologically induced healthspan extension, which I refer to as healthspan pharmacology. Clearly, this omission is a serious one if results from animal studies are to be relevant to humans, many of whom consider their quality of life with advancing age to be just as important as their longevity. There appears to be an emergence of assays in animal models to evaluate healthspan. One of the tests that can be used to evaluate age-related changes in mice, in an effort to quantify the impact of pharmacological interventions on healthspan, is the frailty index (FI), also known as the index of cumulative deficits. ^31,32 A recent study with the goal of evaluating the utility of FI as a tool to evaluate the impact of caloric restriction and resveratrol on healthspan showed that these interventions reduced FI. ³³ There is no obvious reason that this tool could not be used to quantify the effect of other pharmacological interventions on healthspan in animal model studies with the goal of extrapolating the results to humans.

The pharmacological agents that are known to extend lifespan in animal studies appear to act mainly through anti-oxidant defense, protein homeostasis, dietary restriction (DR) modulation, inhibition of kinases, or modulation of insulin/insulin-like growth factor (IGF) signaling. Among numerous agents that have been tested using multiple model systems over the last two decades, the spectrum includes anti-depressants (e.g., mianserin), anti-convulsants (e.g., valproic acid, lamotrigine), anti-diabetics (e.g., metformin), immunosuppressants (e.g., rapamycin), and natural products (e.g., resveratrol, Rhodiola rosea, curcumin, green tea, blueberry). The mechanism of action and the extent of lifespan extension vary among each agent (Table 1), and most can be classified under the aforementioned groups. In addition to the widely known pharmacological interventions that prolong lifespan (e.g., resveratrol, Rhodiola rosea, rapamycin, metformin) across species, high-throughput chemical screening approaches have been used to identify new candidate molecules that extend lifespan in Caenorhabditis elegans and Drosophila melanogaster model systems. ^{14,34 –40} With the convenience of C. elegans and Drosophila as platforms to discover new lifespan–extending compounds, it is inevitable that the number of identified anti-aging compounds that extend lifespan will continue to increase dramatically.

Although the end point of prolonged longevity is clear (i.e., the death of the organism), the physiological mechanisms of extending lifespan via anti-aging interventions have been elusive. The implicit assumption that increasing the mean lifespan of a model organism not only delays aging but also the onset of the age-related physiological effects is unsupported and should be re-evaluated to include measurements of health parameters to determine if an intervention has the potential to add healthy years to the life of the model organism and eventually to humans. Even though a given intervention may extend the lifespan of the organism, if it decreases overall health, it should not be tested in a clinical study to evaluate its potential for human life prolongation, which is the ultimate goal of the longevity research.

The list of studies reporting lifespan extension via pharmacological agents (Table 1) is rather extensive compared to studies where healthspan was also taken into consideration (Table 2). There is no doubt that it is important to identify anti-aging compounds because, aside from their impact on lifespan, they will assist us in elucidating molecular pathways that may impact aging as outlined in Table 1. However, evaluating the impact of such compounds on healthspan is just as important as knowing their impact on lifespan.

The reason for this assertion is rather subtle. Although lifespan and healthspan have been thought to be highly correlated, recent reports indicate that they may not be as closely linked as previously thought. A recent study that uncoupled lifespan and healthspan in C. elegans by examining wild-type and four long-lived mutants provided evidence that in a number of cases, where lifespan was extended, the health of the worms suffered drastically. ⁴¹ Given that life expectancy has been on the rise for humans, further extending lifespan alone without improving healthspan will have significant adverse outcomes, such as unmanageable health care costs due to declined quality of life and increased incidence of age-related diseases, which further underscores the importance of studying healthspan as opposed to just lifespan.

Healthspan Pharmacology

Despite the necessity of evaluating healthspan in the context of lifespan, a comprehensive definition of healthspan in the laboratory requires an all-inclusive approach defining and evaluating a number of physiological parameters that contribute to the state of health. Describing measurable parameters to determine healthspan is more challenging compared to lifespan, which is simply measured by the mean and maximum life expectancy of the organism. A few parameters for healthspan have been utilized for invertebrates model systems. For instance, movement and feeding behaviors have been used as healthspan markers for C. elegans, ^{41 –44} whereas locomotion and reproduction serve as the indicators of health for D. melanogaster. ⁴⁵ Not surprisingly, when it comes to a mammalian model system, such as mice, the definition of healthspan parameters becomes more complex. Even though there are a number of validated tests that measure behavior, locomotion, cognition, and metabolism in young mice, there is no uniform set of tests to measure healthspan in aging mice. A recent perspective article ⁴⁶ put forward several recommendations for measuring healthspan in mice in an effort to provide a unified method of focusing on healthspan in aging research. Perhaps the FI that measures cumulative deficits in mice can also be incorporated to quantify the impact of pharmacological interventions on healthspan. Given the challenge of reproducibility of a specified connection between a compound and lifespan extension among different laboratories around the world, correlating the effects of pharmacological interventions with healthspan will be even more challenging.

In conclusion, to extrapolate the result of any potential anti-aging pharmacological agent from the laboratory model systems to humans, evaluation of healthspan absolutely needs to be part of the equation. This is why we now need to shift the focus of the scientific community studying aging and anti-aging from lifespan pharmacology to healthspan pharmacology.