Experimental Gerontology 58 (2014) 14–18 Contents lists available at ScienceDirect Experimental Gerontology journal homepage: www.elsevier.com/locate/expgero What is an anti-aging treatment? David Gems Institute of Healthy Ageing, and Genetics, Evolution and Environment, University College London, Gower Street, London WC1E 6BT, United Kingdom article info abstract Article history: Key objectives of biogerontology are to understand the biology of aging and to translate scientific insight into in- Received 15 November 2013 terventions that improve late-life health — or anti-aging treatments. In this context, when considering the prob- Received in revised form 25 June 2014 lem of how to effect translational research, it is useful to have a clear, consensus view on what exactly constitutes Accepted 10 July 2014 an anti-aging treatment. This essay critically assesses the understanding of this concept common among Available online 11 July 2014 biogerontologists, and proposes a new definition. A current conception of anti-aging treatment imagines a prima- Section Editor: T.E. Johnson ry cause of aging that is causally upstream of, and the cause of, all age-related pathology. Intervening in this aging process thus protects against the totality of age-related diseases. However, this underlying aging process remains Keywords: an abstraction. By contrast, what is demonstrable is that interventions in model organisms can improve late-life Aging health and extend lifespan. Furthermore, a safe deduction is that treatments that extend lifespan do so by reduc- Biogerontology ing age-related pathology, both florid and subtle. What is currently identifiable about aging (i.e. senescence) is Disease that it is a very complex disease syndrome, likely involving a number of biological mechanisms. Treatments Prevention that substantially extend lifespan must suppress multiple pathologies that otherwise limit lifespan, but whether Translation they suppress the entire aging process remains undemonstrated. A more pragmatic and realistic definition of anti-aging treatment is any preventative approach to reduce late-life pathology, based on the understanding that senescence is a disease syndrome. This definition would encompass preventative approaches aimed at both broad and narrow spectra of age-related pathologies. Its adoption would facilitate translation, since it would shift the emphasis to medical practice, particularly the introduction of preventative approaches. Narrow spectrum anti-aging treatments (e.g. the cardiovascular polypill) could establish a practice that eventually ex- tends to broader spectrum anti-aging treatments (e.g. dietary restriction mimetics). © 2014 Elsevier Inc. All rights reserved. 1. Introduction Arguably, fulfillment of these two objectives, while necessary for translation, is far from being sufficient. This is because relative to con- Pathologies of aging underlie much of the disease burden world- ventional views about the nature of aging, the approach of anti-aging wide. Work on animal models has revealed interventions that lead to therapies is a radical one. Such conventions affect both public and polit- an increase in healthy lifespan (Kenyon, 2010). Such studies suggest ical attitudes towards aging and medical practice. Adoption by the med- that by slowing the underlying process of aging one can achieve broad ical establishment of an anti-aging approach to improve late-life health spectrum protection against diseases of aging (Butler et al., 2008). would involve radical, even revolutionary change. It would, for example, Understandably, there is a strong desire among biogerontologists to involve a re-conceptualization of the nature of aging and the relation- shift from pure to translational research, and to identify paths that ship between aging and disease, the introduction of a preventative ap- would lead to clinical trials of anti-aging therapies. This aspiration proach to age-related disease, a more active role of the patient in underpinned the recent conference Interventions to Slow Aging in managing their own late-life health — and even teaching medical stu- Humans: Are we Ready? held in October 8–13th 2013 in Erice, Sicily dents about the biology of aging (currently medical students are taught (organized by Valter Longo, Luigi Fontana and Donald Ingram). little about the biological basis of the most prevalent cause of disease). In order to promote translational research the meeting was oriented One impediment to translation, noted by one speaker at the confer- to two main objectives. First, to survey the (now) many different ap- ence, Brian Kennedy, Director of the Buck Institute for Research on proaches in the laboratory that have been to extend lifespan in animal Aging, is the lack of clarity and consensus about the definition of anti- models, and seek a consensus about which approaches would be most aging treatment. One might mistake this for a minor issue of semantics, promising to test first in humans. Second, to develop a consensus on but here I will argue the opposite: that a good definition of anti-aging the most appropriate biomarkers of aging to use as a readout of treat- treatment is important not only to clearly define the goals of ment efficacy. biogerontology, but also to enable them to be fulfilled. In this essay, I will first give a brief account of the standard biogerontological concep- E-mail address: [email protected]. tion of anti-aging medicine (at least, as I have understood it), and then http://dx.doi.org/10.1016/j.exger.2014.07.003 0531-5565/© 2014 Elsevier Inc. All rights reserved. D. Gems / Experimental Gerontology 58 (2014) 14–18 15 make a critical assessment of this definition. I will then propose an alter- people die without pathology is absurd: in biological terms, by defini- native definition, one that is, arguably, more realistic and pragmatic. tion, endogenous factors harmful enough to cause death must entail se- vere pathology. Put simply: “No one dies from healthy senescence” 2. Anti-aging treatments: a standard view from biogerontology (Blagosklonny, 2006). The notion of death from “pure aging” (i.e. aging without pathology) is surely a myth. One source of this myth A common conception among biogerontologists of anti-aging treat- may well be that some aspects of aging are more identifiable as pathol- ment is based on a straightforward premise: that a biological process, ogies than others. As examples, one cannot fail to identify cancer and aging, gives rise in later life to a broad spectrum of diseases. This being macular degeneration as pathologies, but this is less the case for so, any intervention that inhibits aging itself will reduce incidence of a sarcopenia and osteoporosis. broad spectrum of late-life diseases (Butler et al., 2008). Consistent Human health has been defined in terms not only of the absence of with this premise, a variety of interventions improve late-life health disease, but also of the presence of a level of function that is typical of and extend lifespan in a range of animal models. For example, dietary human beings of a given age and gender (Boorse, 1977). By this view, restriction (caloric restriction) has long been known to slow aging and given that all old people experience it, aging is a normal process and improve late-life health in rodents, and may be effective in rhesus mon- therefore distinct from disease — despite the fact that it is accompanied keys (Bodkin et al., 2003; Colman et al., 2009; Mattison et al., 2012)and by a broad spectrum of diseases. Clues to a resolution of this paradox possibly humans (Berrington de Gonzalez et al., 2010; Fontana et al., may be found in the evolutionary theory of aging, which provides a bi- 2004). There seems no reason in principle why some form of anti- ological perspective upon the purpose and meaning of the aging process aging treatment should not be efficacious in humans, and lead to great (Caplan, 2005). According to the evolutionary theory, aging is a conse- improvements in late-life health in times to come. Even so, closer scru- quence of a reduction in the force of selection against mutations with tiny of the concept of anti-aging treatment reveals some weaknesses in deleterious effects later in life (Medawar, 1952; Partridge and Barton, this standard view, involving the following questions. 1993). This leads to accumulation within populations of alleles with del- eterious effects later in life — particularly alleles that also have beneficial i) Is there a real distinction between age-related disease and aging? effects on reproductive fitness early in life (Williams, 1957). The evolu- ii) Where should one draw the line between anti-aging treatment tionary theory provides the bleak insight that aging serves no purpose and conventional treatments for late-life diseases? in terms of fitness, but instead is a lethal genetic disease that afflicts iii) To what extent do treatments that extend lifespan in animal all human beings. Arguably, the significance of the universality of models slow aging? human aging is not that aging is not a disease, but rather that it is a spe- iv) Which is a better defining characteristic of anti-aging treat- cial form of disease. To argue that aging is not a disease by virtue of its ments: that they inhibit the central process of aging, or that universality is as unhelpful as it is to argue that the Basenji is not a they prevent age-related diseases? dog because it does not bark. In the next section, I will start by attempting to clarify the relation- In short, senescence is an inherently pathological process. Thus, ship between aging and age-related pathology. “healthy aging” in the sense of “healthy senescence” is an oxymoron. However, in terms of calendar aging or age-related change, healthy 3. The myth of “pure aging” aging is a desirable goal. One reading of the history of ideas on aging is that apologism has generated not only the standard (and nonsensical) Conceptually, the idea of protecting against age-related diseases by medical view of aging as distinct from pathology (“healthy senes- retarding aging remains somewhat fuzzy due to the lack of a clear un- cence”), but also the conception by biogerontologists of pathology- derstanding of what aging actually is.