<i>FOXO3</i>, a Resilience Gene: Impact on Lifespan, Healthspan, and Deathspan

Oliver Wendell Holmes is purported to have said, “Old age is always fifteen years older than I am.” Given recent rapid advances in understanding the aging process – from molecular, cellular, tissue, organ, to whole body aging – Holmes appears prescient. There is little doubt that people age at different rates and in different ways (1). If one could indeed remain 15 to 20 years “biologically younger” than their chronological age and delay the onset of aging-related chronic diseases and disability, that would be quite an achievement for the individual and society (2). This, of course, assumes that if lifespan is prolonged, one also compresses morbidity, resulting in a longer healthspan(definition), not a longer “deathspan” (ie, poor quality of life from extra years of severe disease and incapacitation), see Figure 1. Healthspan vs. Deathspan. To elaborate on “healthspan” and “deathspan”, the former is the number of years free of major disease and disability, while the latter is years with major chronic disease and/or disability. Deathspan can have major public health implications since these are the years that consume the most healthcare resources (42). Moreover, deathspan cannot be reliably predicted at present. Being able to predict the length of deathspan would offer better potential allocation of resources, while providing a more accurate means of measuring and treating aging-associated diseases. This could help to reduce age-associated morbidities. Established biomarkers of physiological aging, such as maximal oxygen consumption (max. V02) for cardiovascular aging and forced expiratory volume1 (FEV1) for pulmonary aging, have been well studied and decline at a predictable rate in humans (3). Those fortunate enough to have a genetically more resilient physiological system, may start with a higher baseline function and/or undergo functional decline more slowly. Importantly, the biological rate of aging for an individual organ or physiological system, can be decelerated or accelerated by non-genetic factors, such as smoking, poor diet, and lack of exercise, among other modifiable “lifestyle” factors (1). Geroscience is becoming ever closer to having phenotypic tools capable of measuring the rate of human aging at multiple system levels. For example, 258 candidate blood-based biomarkers of aging and age-related disease were reviewed by an expert panel for the Targeting Aging with Metformin (TAME) clinical trial (4). About 10 biomarkers made the cut for consideration based on reliability and feasibility, relevance to aging hallmarks, consistently robust in prediction of outcomes (all-cause mortality, clinical and functional utility), and for potential responsiveness to the study intervention. With accurate and reliable measures of aging processes, gauging the “success” of a biological age-modifying intervention is now within reach. An individual’s genetic make-up has long been known as a strong predictor of lifespan. For example, offspring or siblings of centenarians are predisposed to longevity (5). The heritability of human lifespan is still hotly debated, but twin research suggests it is about one third, two-thirds being non-genetic factors (eg, diet, exercise, smoking) (6). The current Special Issue focuses on one such genetic factor – FOXO3 genotype (also known as FOXO3A). The gene FOXO3 is one of only two human genes that has shown consistent replication for association with longevity across multiple human populations. The other is, of course, the apolipoprotein E gene (APOE) (7). These genes might be referred to as the “A list” since no other single gene comes close for relation to human longevity. But with the sheer number of ongoing genetic studies of human aging and longevity this is a rapidly moving target (8). The history of genetic studies of human aging and longevity is short. While one could argue about who did what study first, there is a clear progression of studies utilizing centenarians as a model of exceptional human aging and longevity. This began in the 1980s with the Okinawa Centenarian Study (OCS) (9). The OCS was among the first of several large-scale centenarian studies and is the longest continuously running centenarian study in the world. In 1987, the OCS conducted the first candidate gene study of human longevity and discovered that alleles of several HLA genes were positively or negatively associated with longevity, defined as surviving to nonagenarian and/or centenarian years (10). This seminal study led directly to another widely hailed study in the 1990s utilizing similar methodology but comparing genotypes of French and German centenarians with younger aged controls. In this study, Schachter and colleagues were the first to discover the link between alleles of APOE and human longevity (11). This finding was replicated thereafter in multiple populations (7). Despite many subsequent studies, only APOE stood out as a highly replicated “longevity” gene until the discovery of the FOXO3-human longevity link. In 1988, Friedman and Johnson discovered a recessive mutation in a gene in Caenorhabditis elegans (C. elegans), a nematode model organism widely used in aging research (12). This gene, age-1, was associated with a 40% to 65% increase in lifespan and a significantly reduced mortality rate, compared to controls, suggesting slower aging (13). The fact that one gene could influence the rate of aging in a model organism of aging was a seminal finding. It led others to explore potential mechanisms and to find aging-related pathways, such as the insulin/IGF-1 genetic pathway (14). This pathway emerged as the first aging-related genetic pathway discovered in any organism. It started with the finding by Kenyon and colleagues in 1993 of a long-lived C. elegans mutant in the gene daf-2 (15). This mutant’s life extension was the longest reported in any organism at that time and required a second gene, daf-16 – the homologue of human FOXO. Morris and colleagues, from Gary Ruvkun’s t