The Quarterly Review of Biology

Volume 79, No. 1 March 2004 The Quarterly Review of Biology MEAT-ADAPTIVE GENES AND THE EVOLUTION OF SLOWER AGING IN HUMANS Caleb E. Finch Andrus Gerontology Center and Department of Biological Sciences University of Southern California Los Angeles, California 90089 USA e-mail: cefi[email protected] Craig B. Stanford Jane Goodall Research Center, Departments of Anthropology and Biological Sciences University of Southern California Los Angeles, California 90089 USA e-mail: [email protected] keywords aging, apolipoprotein E, chimpanzee, diet, evolution, great apes, human, hypercholesterolemia abstract The chimpanzee life span is shorter than that of humans, which is consistent with a faster schedule of aging. We consider aspects of diet that may have selected for genes that allowed the evolution of longer human life spans with slower aging. Diet has changed remarkably during human evolution. All direct human ancestors are believed to have been largely herbivorous. Chimpanzees eat more meat than other great apes, but in captivity are sensitive to hypercholesterolemia and vascular disease. We argue that this dietary shift to increased regular consumption of fatty animal tissues in the course of hominid evolution was mediated by selection for “meat-adaptive” genes. This selection conferred resis- tance to disease risks associated with meat eating also increased life expectancy. One candidate gene is apolipoprotein E (apoE), with the E3 allele evolved in the genus Homo that reduces the risks for Alzheimer’s and vascular disease, as well as influencing inflammation, infection, and neuronal growth. Other evolved genes mediate lipid metabolism and host defense. The timing of the evolution of apoE and other candidates for meat-adaptive genes is discussed in relation to key events in human evolution. The Quarterly Review of Biology, March 2004, Vol. 79, No. 1 Copyright ᭧ 2004 by The University of Chicago. All rights reserved. 0033-5770/2004/7901-0001$15.00 3 4 THE QUARTERLY REVIEW OF BIOLOGY Volume 79 URING THE LAST several million rizes the substantial demographic data and D years, our human ancestors evolved two the sparse information on physical and major changes in life history that would behavioral changes in aging chimpanzees appear to be mutually antagonistic: a shift with reference to human norms. Wild and from vegetarian to meat-rich diets and an captive animals are distinguished, because increase in adult life expectancy. “Meat eat- the latter are often fed dairy and meat prod- ing” as used here represents all animal tissues, ucts that may promote chronic disease, as dis- includes fat, bone marrow and brains, as well cussed in detail below. as skeletal muscle. The major increase in Relative to humans, chimpanzees have a meat eating in human ancestors would be 30-year shorter life span and an earlier accel- expected to elevate blood cholesterol, which eration of mortality rate (Goodall 1983, 1986; is a risk factor in both Alzheimer’s disease and Kaplan et al. 2000; Hill et al. 2001) (Table 1, vascular disease. Other hazards of meat-rich Note 1). The maximum life span of chimpan- diets include diet-induced hypercholesterol- zees is about 60 years. At age 15, the chim- emia and infections. Thus, the increases in panzee life expectancy is about 15 more years meat eating would be predicted to shorten in the wild. In contrast, human foragers have life expectancy by promoting chronic dis- a life expectancy at age 15 of 40 more years. eases. We propose that meat-adaptive genes Hill et al. (2001) concluded that the mean were evolved to delay dysfunctions and dis- adult life span of chimpanzees was about 60% eases of brain and heart caused by this shorter than hunter-gatherers and that man- increasingly meat-rich diet. We then consider ifestations of senescence begin about 20 years candidates for meat-adaptive genes that earlier. However, mortality rate differences would favor long life spans by minimizing between species or populations may not cor- acute and chronic diseases. Much is known respond directly to functional changes dur- about the unique human allele of apolipo- ing aging. For example, the age of meno- protein E, the apoE e3 allele (“apoE3”), which pause has changed very little during the last decreases the risk of Alzheimer’s and vascular 200 years in Europe and North America (Gos- disease in aging adults. We discuss the timing den 1985; vom Saal et al. 1994), despite the of evolution of apoE and other genes in rela- major increases in adult life expectancy. tion to anatomical and physiological changes Longitudinal studies of wild chimpanzees in our human ancestors that enabled began at Gombe National Park (Tanzania) in increased hunting and meat eating. This dis- 1960 by Goodall (1983, 1986) and show frailty cussion extends the arguments in Finch and and weight loss in individuals aged 35 or Sapolsky (1999) that the evolution of pro- more (Table 1, Note 2). External indications longed reproductive schedules, intergenera- of senescence include sagging skin, slowed tional knowledge transfer, and slowed aging movements, and worn teeth. Longitudinal in humans relative to chimpanzees selected life histories are being recorded in many for apoE3. First, we evaluate the evidence for other African sites, but a more complete geri- faster aging in chimpanzees. Supplemental atric profile of wild animals is needed for information is given in the Appendix. comparison with the ongoing studies of cap- tives (e.g., the Great Ape Aging Project: FCCB Life Expectancy and Aging in 2002). Chimpanzees Postmortem studies of wild chimpanzees The aging patterns of chimpanzees and are largely restricted to skeletal remains. other great apes are very incompletely char- Bone thinning (osteopenia) may be earlier acterized (Cyranoski 2002; Hof et al. 2002; and more extensive than in modern humans NHGRI 2002). Of the species closest to (Table 1, Note 9). Lovell (1990a, 1990b, 1991; humans (Pan sp.), the chimpanzee (Pan trog- Lovell et al. 2000) showed in detail that trau- lodytes) has been studied longer and in more matic bone injury from fractures and pierc- detail than the bonobo (P. paniscus). Evi- ing wounds are very common in adults (Table dence is consistent that survival beyond 50 1, Note 10). Intriguingly, osteoarthritis was years is rare in both species. Table 1 summa- rarer than in most human populations (Table March 2004 MEAT-ADAPTIVE GENES AND EVOLUTION 5 1, Note 8), which Jurmain (2000) suggests hyperplasia (BPH), according to a laboratory may be due to better load distribution from study that was unique by its sizable sample quadrupedal locomotion. Dental malfunc- and rigorous clinical criteria (Steiner et al. tions that would impair food ingestion are 1999) (Table 1, Note 13). BPH occurred in common, due to tooth wear from mastication 70% of males aged 30 or older. Serum pros- of abrasive plant foods; tooth breakage and tate specific antigen (PSA) increased pro- abscesses; and tooth loss from fighting (Table gressively during aging and in correlation 1, Notes 2 and 11, and Appendix). To survive, with the degree of BPH. These findings sug- wild chimpanzees must contend with the cost gest a 20-year earlier onset of senescence in of accumulated injuries to bones and teeth, male chimpanzees than in men. as well as to soft tissues. Brain-aging changes are mild in laboratory Reproduction persists to advanced ages, chimpanzees relative to the devastations of despite indications of lengthened cycles and Alzheimer’s disease in humans. Preliminary perimenopausal changes (Table 1, Note 12 findings do not show neuron loss or shrink- and Appendix). At Gombe, one mother and age (Erwin et al. 2001). The postmortem her daughter, both high ranking, remained diagnosis of Alzheimer’s disease is based on fertile until after 40 years; the subsequent ces- localized neurodegeneration in the frontal sation of sexual swellings strongly implies per- cortex and hippocampus, with neurofibril- imenopause. The late age fertility of these lary tangles and senile (neuritic) plaques con- individuals may be unusual, because in taining amyloid b-peptide (Ab) mingled with humans natural fertility declines sharply after degenerating neurites. Humans with Alzhei- age 40 due to loss of oocyte quality as the ovar- mer’s disease, and to a lesser extent during ian stock of oocytes enters the final stages of normal aging, also have extracellular Ab depletion (Gosden 1985; vom Saal et al. 1994; deposits around cerebral blood vessels (amy- Burger et al. 2002). In captivity, lengthened loid angiopathy) (see Table 1, Note 5 and the menstrual cycles may continue up to 50 years, Appendix for criteria of Alzheimer’s disease just before death. The ovaries of aging chim- and controversies about Ab). Two of the three panzees and bonobos show very extensive aging chimpanzee brains showed amyloid oocyte depletion (Graham 1979; Graham et angiopathy and some senile plaques contain- al. 1979; Gould et al. 1981). Oocyte depletion, ing Ab in the same places afflicted in Alzhei- as in human menopause, was apparently com- mer’s disease (Table 1, Notes 4 and 5). There plete in one individual, who had no active was no evidence of neurofibrillary degenera- luteal tissues or growing follicles (Gould et al. tion, however (Table 1, Note 6). In contrast, 1981). The very late menopause in chimpan- the grey mouse lemur, rhesus monkey, and zee, when it occurs, allows for a relatively some other primates develop more typical short postmenopausal phase before death. Alzheimer changes during aging (reviewed in Reproductive aging in other primates is sur- Finch and Sapolsky 1999). Although more veyed in Table 1 (Note 12) and the Appendix. chimpanzee brains must be evaluated at later As proposed by Hawkes et al. (1998), ages, it is possible that chimpanzees and other humans have evolved a prolonged postmeno- great apes have less intense Alzheimer-type pausal phase, not found in the other great changes because their apoE gene sequence apes.

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