Linking Nutrition, Maturation and Aging: From Thrifty Genes to the Spendthrift Phenotype

Nearly 50 years ago geneticist James Neel famously proposed that “thrifty genes” were important contributors to the rising prevalence of diabetes [1]. Such genes promote efficient use and conservation of food energy, he theorized, and thus were favored by natural selection to help our ancient ancestors cope with famines. Now widespread in various populations, they predispose to obesity and diabetes, abetting a tendency to prepare for famines that never come. Though intuitively appealing, the theory has often been challenged. Perhaps the strongest objection has been that there's little evidence our ancestors faced frequent, high-mortality famines that would have selected for thrifty genotypes [2]. Recently, the theory's proponents have countered that thrifty genes' selective advantage probably had more to do with fertility than survival—women who rapidly deposited fat during periods of adequate nutrition would have been able to sustain relatively high reproductive rates during lean times and make larger contributions to the gene pool [3,4]. Here I propose an extension of this reproduction-centered version of Neel's theory that bears on aging. One of my key premises is that many windows of opportunity for reproductive booms occurred during the Holocene as agricultural innovations spread, periodically increasing food availability between times of nutritional stress. The periods of plenty selected for genotypes capable of rapidly ramping up fecundity as food intake increased. Sexually mature females would have quickly added fat—a certain level of maternal body fat is critical for reproduction [5]. Prepubertal females would have similarly added fat in conjunction with the acceleration of development and earlier onset of sexual maturity. I believe the boom times' selection of genotypes prone to nutrition-cued accelerated development is having an especially problematic effect today because of widespread childhood overnutrition. Accelerated development, which enhanced reproductive success in the past, now has a pro-aging effect with rapidly growing costs. Indeed, when viewed through the lens of the antagonistic pleiotropy theory of aging [6], this effect seems anything but thrifty: It predisposes toward what might be called the spendthrift phenotype, characterized by chronic activation of pro-growth pathways—notably those involving mTOR, insulin, and insulin-like growth factor-1—that support rapid development and sexual maturation but that also underlie later senescence [7]. The modern fallout encompasses a much broader array of age-associated ills than the diabetes that prompted Neel's original hypothesis. Indeed, the spendthrift phenotype may well increase the age-associated risks of most if not all diseases of aging, like the ruinous adult legacy of flush, fast-living youth. The selective pressure exerted by famines Neel's proposal that past famines reduced survival of individuals lacking thrifty genotypes has been invoked to explain, among other things, epidemic rates of type 2 diabetes that developed among various new-world populations after their adoption of western diets and lifestyles, such as the Central Pacific's Nauru Islanders [8,9]. However, it seems unlikely that Pacific island populations, dwelling on luxuriantly vegetated islands surrounded by fish-rich temperate waters, would have faced much risk of catastrophic famine [10]. Speakman argues that severe famines have generally been rare demographic events, occurring about once a century (mainly after the advent of agriculture-based societies), and that, in any case, they have usually posed a limited threat to viability, causing excess annual mortality of perhaps 5%, much of which has affected old, post-reproductive adults whose differential mortality plays no role in natural selection [2]. Fixing this weak link in Neel's original argument, thrifty-gene proponents, notably Prentice and colleagues, have emphasized the high selective intensity engendered by differences in fertility [4]. Nutritional stress potently suppresses fertility, they observe, and even seasonal food shortages in the developing world reduce conceptions by 30% to 50%. Although catastrophic, high-mortality famines may have been rare, there's considerable evidence that milder ones have frequently occurred during the Holocene [3,11]. The agricultural revolution that began about 12,000 years ago augmented the risk of famines as growing sedentary populations increasingly relied on a limited number of food sources vulnerable to droughts, diseases, and other threats. Shortages would have favored genotypes less vulnerable to curtailing of reproduction by nutritional stress. (Fertility is suppressed in women when fat stores fall below about 22% of body weight [5].) Moreover, a pan-human tendency to store energy as fat to enhance reproduction probably existed long before the Holocene. As Wells notes, humans and their Homo ancestors are, in essence, “colonizing apes” whose global spread was likely aided by such a tendency [12]. Ample energy reserves would have enabled uninterrupted fertility during colonization of nutrition-ally parlous territories. Big brains make large energy demands, and meeting that demand is especially critical during early development. (Newborns' brains may account for 80% of basal energy metabolism [13].) Homo females' energy thrift, including the deposition of larger fat stores than males, was probably critical for sustained fertility and nursing of big-brained infants in marginal environments. It should be noted that nutritional stress needn't select exclusively for adipogenic thrift. Other forms of metabolic and behavioral plasticity, such as a tendency to hoard food or to increase foraging avidity, could buffer vicissitudes in food supply [12]. (The induction of “hard foraging” behavior in rodents by calorie restriction may represent a case of such plasticity [14].) The ability of offspring to match their levels of energy demand to maternal energy supplies might facilitate the evolving of diverse strategies to cope with energy stress [12]. Such diversity may underlie the variability in adiposity observed across modern populations.