Discussion Lifespan is not determined by metabolic rate: evidence from fishes and C. elegans Kelvin Yen, Jason W. Mastitis, Charles V. Mobbs * Fishberg Center for Neurobiology, Neurobiology of Aging Laboratories, Department of Geriatrics, Mount Sinai School of Medicine, Box 1639, One Gustave L. Levy Place, New York, NY 10029, USA Roy Walford is best known for his work in the immunology of aging and mechanisms of caloric restric- tion, mainly in mice (and, later, humans), but interestingly, much of his early research in gerontology focused on the effects of temperature on lifespan in fishes (Walford et al., 1969; Liu and Walford, 1972, 1970, 1975; Liu et al., 1975). Although it had been known since 1916 that reducing temperature in poikilotherms would increase lifespan (Loeb and Northrop, 1916) (paper in which Drosophila was first used in gerontological research), this paper, and many papers subsequently demonstrating this effect in numerous other poikilotherms, essentially attributed the effect to physical effects, viz., a reduction in enzyme and/or metabolic rates. Under the sway of the rate-of-living theory, very few if any subsequent studies actually tested this hypothesis, which was considered so obvious as to not require testing. In 1962, the year of his very first (essentially theoretical) paper concerned with aging (Walford, 1962), Walford undertook an expedition to South America specifically to obtain fish to study basic mechanisms mediating the process of aging. His motiv- ation for using fish rather than other more traditional models for aging (including Drosophila) was that his ultimate goal was to assess his immune theory of aging, and in his view this required the use of vertebrates. On the other hand he obviously intended from the beginning to study mechanisms by which temperature extends lifespan, so he needed a poikolotherm vertebrate. The idea to use fish apparently came from Alex Comfort (before Comfort got really famous), but the idea of using fish to examine mechanisms mediating the effect of temperature on lifespan seems to have been purely his own. The first paper reporting studies with these fish and published in 1965 (Walford and Liu, 1965) is a true classic and addresses many important aspects of the aging process. With a lifespan (a little more than 1 year) and a pattern of reproductive senescence (easily quantified by the rate of egg-laying) and body weight changes very similar to those of rodents, this paper convincingly demonstrated the utility of fish for studying fundamental process of aging. Adiposity (as indicated by body weight per unit length) did not increase with age, and indeed decreased with age after about a month before significant mortality began, thus arguing against increased adiposity as a universal con- comitant of aging and arguing against adiposity as a necessary risk factor for mortality. Most importantly, the paper demonstrated that lower temperature increased lifespan (the first paper to demon- strate this phenomenon in vertebrates) while at the same time increasing growth rate. Indeed, the lower temperature not only increased growth rate, it appeared to increase final adiposity by over 60%. Thus, increased lifespan was actually associated with increased adiposity, providing early evidence against the widely held hypothesis that effects of caloric restriction are due to reduced adiposity, later convincingly disproved by Harrison (Harrison et al., 1984). That the increased lifespan was actually due to a fundamental change of the aging process was indicated by the observation that reproductive senescence was also greatly delayed at the lower temperature. The pathological analysis (Walford was in the department of pathology), one of the most thorough we have ever encountered in a gerontological report, corroborated that the lower tempera- ture retarded the rate of aging; for example, lower temperature delayed (or prevented) decreases in spinal curvature, eye cataracts, and scale alterations that occurred during aging at the higher temperature. Regarding the implications of these observations, Walford’s comment is quite revealing: “Differences in growth rates and aging rates at different temperatures are not easy to explain physio- logically. More complex processes than simply a ‘slowing 0531-5565/$ - see front matter q 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.exger.2004.03.016 Experimental Gerontology 39 (2004) 947–949 www.elsevier.com/locate/expgero * Corresponding author. Tel.: þ 1-212-659-5929; fax: þ1-212-849-2510. E-mail address: charles.mobbs@mssm.edu (C.V. Mobbs).