Genome wide association studies GWAS for longevity

Genome-wide association studies (GWAS) for longevity and healthy aging have only recently moved to the fore in gerontology research. The first consistent association with longevity emerging from GWAS is APOE (Schachter et al., 1994), a gene that has established links to Alzheimer\'s disease (Beecham et al., 2009). APOE has subsequently been linked to a variety of conditions and a lipoprotein metabolic theme appears to be shared among the major disorders of aging (Johnson et al., 2015). GWAS has also been applied to identify determinants of circulating lipid levels, the European Network for Genetic and Genomic Epidemiology (ENGAGE) conducted a meta-analysis to identify neuron specific enolase associated with serum lipid burden where many of the candidate genes aligned beautifully with the known biology of lipid metabolic regulation in addition to novel roles for genes previously unidentified as being involved in lipid biology (Aulchenko et al., 2009). Studies investigating genetic determinants of body fat distribution identified numerous new genes of interest, confirming the long suspected links between adipose tissue and metabolic dysfunction (Locke et al., 2015; Shungin et al., 2015). Studies of complex traits have also proved informative, for example the Cohorts for Heath and Aging Research in Genomic Epidemiology (CHARGE) consortium used a combination of GWAS with subsequent quantitative trait locus (QTL) analysis to identify several genes associated with variance in gait speed (Ben-Avraham et al., 2017). Network analysis linked these genes to growth and inflammatory signaling, including factors involves in ion transport, metabolism, and cell structure. A similar study of dynapenia, the loss of muscle strength, identified CEBP (CCAAT/enhancer-binding protein beta) as a possible determinant in grip strength, which is interesting as it had already been linked to muscle repair (Matteini et al., 2016). Generally the percentage of variance in population phenotypes explained by GWAS identified candidates is on the small side; however, the alignment between the biology of these genes and the traits they influence is undeniable, and the possibilities for new insights into the biology of disease incidence and progression using this unbiased approach are beyond that promised by any other type of analysis to date. As more genomic data become available for analysis we can expect further discoveries into the genetics of human aging using advanced computational methods to integrate across studies. These studies are expected to point to the causative agents in disease vulnerability, opening up studies into the underlying biology of these factors and how they interact with age and environment to determine longevity.
Caloric Restriction Studies Since McCay\'s initial documentation (McCay et al., 1935), calorie restriction has endured 80years of research to stand out as the most robust dietary intervention to extend average and maximum lifespan and delay the onset of age-related pathologies (Anderson and Weindruch, 2012). The effect of CR on longevity is conserved across a diverse range of species from unicellular organisms such as yeast to nematodes, invertebrates and mammals. To date a range of factors have been associated with the beneficial effects of CR, a small subset of which are discussed in the next section. As with any pursuit in medical research, confirmation of the translatability of beneficial outcomes established in studies of short-lived rodents species to humans is the litmus test. The translational gap from lab to clinics can be bridged by studies in nonhuman primates, which share a high degree of similarity to humans. Rhesus monkeys (Macaca mulatta) share 93% identity with humans at the genetic level (Zimin et al., 2014), and are highly similar in anatomy, physiology, and endocrinology (Colman and Anderson, 2011). Average lifespan for rhesus monkeys in captivity is ~26years of age and the maximum lifespan reported nationally is ~40years of age. Importantly incidence and prevalence of age-related diseases and the impact of age aligns nicely for humans and rhesus monkeys. Unlike rodents, rhesus monkeys display patterns of eating and sleeping behavior that mirror those of humans, and the aging trajectory is gradual, also like that of humans, beginning in middle age. In contrast to human studies, rhesus monkey studies can be designed to facilitate comprehensive monitoring of subjects and strict adherence to the study protocol. Given the high degree of translatability and the tractability in study design, nonhuman primates are a vital link between basic research and clinical application.