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J Comp Physiol B (2008) 178:439–445 DOI 10.1007/s00360-007-0237-5 R EV IE W Negligible senescence in the longest living rodent, the naked mole-rat: insights from a successfully aging species Rochelle BuVenstein Received: 11 September 2007 / Revised: 8 November 2007 / Accepted: 5 December 2007 / Published online: 8 January 2008 © Springer-Verlag 2007 Abstract Aging refers to a gradual deterioration in function that, over time, leads to increased mortality risk, and declining fertility. This pervasive process occurs in almost all organisms, although some long-lived trees and cold water inhabitants reportedly show insigniWcant aging. Negligible senescence is characterized by attenuated agerelated change in reproductive and physiological functions, as well as no observable age-related gradual increase in mortality rate. It was questioned whether the longest living rodent, the naked mole-rat, met these three strict criteria. Naked mole-rats live in captivity for more than 28.3 years, »9 times longer than similar-sized mice. They maintain body composition from 2 to 24 years, and show only slight age-related changes in all physiological and morphological characteristics studied to date. Surprisingly breeding females show no decline in fertility even when well into their third decade of life. Moreover, these animals have never been observed to develop any spontaneous neoplasm. As such they do not show the typical age-associated acceleration in mortality risk that characterizes every other known mammalian species and may therefore be the Wrst reported mammal showing negligible senescence over the majority of their long lifespan. Clearly physiological and biochemical processes in this species have evolved to dramatically extend healthy lifespan. The challenge that lies ahead is to understand what these mechanisms are. Communicated by I.D. Hume. R. BuVenstein (&) Department of Physiology and The Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, 15355 Lambda Dr STCBM 2.2, San Antonio, TX 78245, USA e-mail: [email protected] Keywords Slow aging · Maximum lifespan · Oxidative stress · Reproduction · Heterocephalus glaber Abbreviations MLSP Maximum lifespan LQ Longevity quotient BMR Basal metabolic rate ROS Reactive oxygen species Introduction Aging remains one of the most poorly understood biological phenomena. This is partially because it is an inherently integrative and complex process, further complicated by the diYculty in separating the eVects of normal aging from those manifested as a consequence of age-associated diseases. Aging, deWned as a progressive, irreversible, endogenous and deleterious process (Strehler 1962), induces a decline in physiological and reproductive capacity. Over time, this turns young healthy adults into older, frail and less fertile adults who are increasingly susceptible to environmental challenges (such as extreme temperature, or disease-inducing infectious agents) with a concomitant greater risk of dying (Miller 1999; Martin 2006). The progressive character of aging suggests that causes are present throughout adult life and rates of aging may be discerned at all ages, enabling the distinction of the young from old throughout the animal kingdom. The endogenous nature of aging implies that mechanisms that determine or limit its rate are encoded in the genome, and most likely constitute a suite of genetically determined somatic maintenance mechanisms that may serve as maximum species lifespan (MLSP) determinants under ideal conditions. The ability for the genome to evolve these mechanisms that ensure 123 123 30 Naked mo le- rat 20 10 0 0 2 4 6 8 10 12 L n Ma s s ( g ) Fig. 1 Maximum lifespan (MLSP) as a function of body mass of rodents. Please note that the naked mole-rat MLSP lies more than two standard deviations away from this descriptor 5 Longevity Quotient longevity, however, can only be expressed when the species is protected from extrinsic factors (e.g., predation and climatic extremes). While extrinsic factors such as environmental stressors, (e.g., toxic chemicals) may contribute to the aging process, enhancing or diminishing endogenous eVects, they, themselves, are not determinants of MLSP. Maximum species lifespan is considered an important species characteristic of the aging process. Reported MLSP varies more than 40,000-fold across the animal kingdom and even within mammals MLSP varies by two orders of magnitude. Generally MLSP lengthens in a predictable manner as species increase in size, such that for every doubling of body mass, there is, on average, a 13% increase in MLSP for non-volant, non-aquatic mammals (de Magalhaes et al. 2007). Even in that tightly controlled study where only veriWed lifespan data from the newly formed “Anage web site” were used, and aquatic cetaceans and volant bats omitted from regression analyses, a large proportion of the variation (>50%) is not explained by body mass. Rather MLSP appears to be taxon speciWc such that within mammals cetaceans, primates and bats have higher longevity quotients (LQs—i.e. the ratio of observed lifespan to that predicted by size for non-volant mammals), while marsupials are shorter-lived (de Magalhaes et al. 2007). Longevity may also be dependent upon ecological variables that inXuence extrinsic mortality (Ricklefs 1998): subterranean animals, protected from both climatic extremes and predation, tend to live longer than the aboveground dwelling similar-sized species (BuVenstein 2005) and similarly, Xying mammals that rest in inaccessible localities (e.g. caves) and avoid land predators by Xying are also extremely long-lived (Austad and Fischer 1991). Extended longevity is also correlated with group or social living, such that bats that live in large roosts, social primates, colony dwelling mole-rats, and the eusocial insects (honey bees, wasps, and ants) all show extended longevity (Carey and Judge 2001; BuVenstein 2005; Keller and Jemielty 2006). Enhanced Wtness and prolonged longevity in these species may reXect intergenerational transfer of information, communal care of young and shared foraging endeavors (BuVenstein 2005). Within some taxa certain species conspicuously stand out as being exceptionally long-lived. One such species is the naked mole-rat, the longest-living rodent known (Fig. 1); with a LQ that far exceeds any other rodent species (Fig. 2). Naked mole-rats (Rodentia: Bathyergidae; Heterocephalus glaber) are mouse-sized (»35 g) hystricognath rodents, that in captivity live more than 28.3 years (BuVenstein and Jarvis 2002). Not only can we glean considerable insight into the various evolutionary theories of aging (alluded to above), but this species may also provide information about the timing of age-related declines, and mechanisms employed during the ubiquitous aging process. J Comp Physiol B (2008) 178:439–445 Maximum lifespan (y) 440 N a k e d m o l e - r at 4 3 2 1 LQ=1 0 0 2 4 6 8 10 12 L n M as s ( g ) Fig. 2 Longevity quotients of rodents. These values are determined using the observed MLSP and the lifespan values predicted from the relationship between maximum lifespan and body mass (as determined from de Magalhaes et al. (2007) equation (MLSP = 3.34 M0.193 (g) for all mammals excluding cetaceans and bats). A longevity quotient of 1 means that observed MLSP is similar to that predicted by body size. The naked mole-rat is an extreme outlier from the general trend, living Wve times longer than expected by mass It was speciWcally questioned whether this exceptionally long-lived rodent, like marine inhabitants from cold aquatic environments (Finch and Austad 2001) showed signs of negligible senescence at both physiological and biochemical levels. Negligible senescence was a term coined by Caleb Finch (1990), to describe the very slow aging reported in coldwater Wsh, bivalves, turtles and whales. Many of these organisms, aged by growth zone analyses of the otolith, ear bone or shell, are thought to live for more than 100 years. Caleb Finch proposed three speciWc criteria to test the occurrence of negligible senescence, namely no observable: (1) age-related increase in mortality rate, (2) decrease in reproduction rate after maturity, and (3) no agerelated decline in physiological capacity. This paper reviews the data attained to date which leads us to ask if the naked mole-rat may be the Wrst known mammal to show signs of negligible senescence over the major proportion of its long lifespan. If so how is this species able to exhibit retarded rates of aging. J Comp Physiol B (2008) 178:439–445 441 Mortality rates of naked mole-rats are highest in their Wrst 2 months of life, and death in this age cohort is generally attributed to inadequate maternal care, cannibalism by siblings and poor inoculation of gastrointestinal Xora and fauna. Thereafter, age-speciWc rates of mortality are not evident, with random distribution of deaths by natural causes in all age groups. It is extremely diYcult to plot mortality curves for our colonies, as the animals were routinely used in experiments or individuals were removed from colonies to found new colonies and many of our earlier cohorts were given to other researchers and zoos, while colonies may continue to expand through successful reproductive endeavors. Therefore, data from wild-caught animals and animals born in the Wrst year in captivity are presented in Fig. 3. Of these 86 animals, 43% were still alive 24 years later, when a building malfunction resulted in the animal facility overheating thereby accidentally killing all the animals housed in that room. Looking at this Wgure it is evident that there is no speciWc increase in age-related mortality over a 24-year period. Mortality reports collated over a single year (to assess the impact thereof on the proportion of the age cohort of the population that was still alive) revealed a similar percentage of still living animals at 7% (n = 87), 35% (n = 89), 53% (n = 19) and 85% (n = 27) of maximum lifespan (Fig. 4), despite the smaller number of total animals in the older age cohorts. Sherman and Jarvis (2002) also reported that 87% of the animals that they had identiWed as more than 15 years of age (ranging from 15 to >26 years) were still alive 2 years after their initial analyses. Deaths occur with equal low frequency in all age-cohorts and do not follow the expected actuarial aging pattern of increasing mortality as animals exceed 50% of their maximum lifespan (Fig. 4). Although we do not house naked mole-rats in a barrier facility, we seldom Wnd sick animals and to date, have not 100 % Alive 80 60 40 20 Proportion of age cohort (%) Age-related changes in mortality rate % alive % dead 100.0 80.0 60.0 40.0 20.0 0.0 7 35 53 85 Proportion of MLSP (%) Fig. 4 Percentage of animals out of the total population age cohort that were alive (grey bars) or died (black bars) of natural causes over a 12-month-period. Age cohort data are expressed as a percentage of MLSP. Relative annual death rates at 7% of MLPS (2 years of age, n = 87), 35% (10 years, n = 89), 53% (15 years, n = 19) and 85% (24 years, n = 27) were similar observed a single incidence of cancer in our large colony (n = 800 animals). Naked mole-rats do not show the typical age-associated acceleration in mortality risk that characterizes nearly every other mammalian species for which detailed survival data are available. Our unusual mortality pattern may reXect the low susceptibility of these animals to cancer and disease and may also indicate that naked mole-rats may live longer than our current MLSP record. It appears that naked mole-rats show few signs of agerelated mortality until very late in life, and may show a sudden increase in death near the MLSP. Although this has not been previously reported for mammals, this pattern has been observed for a number of insects (e.g. mayXies) that reproduce only once, shortly before they die (Carey 2002). Death in these semelparous organisms, however, appears to be primarily determined by reproductive activities rather than aging per se. Although, it is possible that iteroparous organisms may also show this sudden death at late age, to date there are no published lifespan data that show this type of pattern and all the published data for mammals show gradual age-related increases in mortality rate. The oldest cohort in my naked mole-rat colony (>27.5 years) is now beginning to show pronounced signs of aging and are less active and appear frail. It is therefore most likely that these captive caught individuals are near the end of their lifetime and that they possibly will show a sudden increase in death very near their MLSP, rather than the typical gradual agerelated increase in mortality. 0 0 5 10 15 20 25 30 Min Age (y) Fig. 3 Using data from our original Weld caught population and those born the Wrst year in captivity, the frequency of death by natural causes in each age cohort is plotted. Please note that at the end of this monitored period 39 individuals older than 20 years of age were still alive Reproductive function and age A trade-oV between fecundity and life expectancy is an integral component of most evolutionary theories of aging (Ricklefs 1998). The antagonistic pleiotropy theory of 123 442 J Comp Physiol B (2008) 178:439–445 aging posits that natural selection has favored genes conferring short-term beneWts to the organism at the cost of deterioration in later life. This forms the basis of the disposable soma theory of aging as outlined by Kirkwood (1977) that suggests that animals either partition more energy to somatic maintenance, or partition more energy into reproductive processes. They therefore have greater reproductive output over a shorter period and because their tissues are not adequately maintained, die young. On the other hand, those animals that do not reproduce immediately but rather maintain, and repair their soma, lived longer. The vast majority of individuals in a naked mole-rat colony never reproduce (Jarvis 1981). Those that do become dominant breeding females, however, show no diVerence in captive lifespan to those that never breed (Table 1; Sherman and Jarvis 2002; BuVenstein 2005) and generally continue to breed until they die. Once they become established breeding females and have completed their reproductive growth surge of lumber vertebrae (O’Riain et al. 2000), reproductive output increases with age as a result of larger litter sizes in well-established breeders (Table 2). Indeed our most successful captive born breeding female reproduced for the last 11 years of her life, and reared more than 900 babies in her 23.66 years life time (BuVenstein and Jarvis 2002). An age-related decline in reproductive fertility was not evident since she produced 21 pups in her last litter. Indeed most of the established breeding females over 20 years of age produce very large litters (Table 2), indicative of sustained fertility in later life. While elderly breeding females tend to have very large litters, many of the pups born to elderly females die before weaning. This may be due to inadequate maternal milk production or greater disturbance in larger colonies where the older well-established breeders tend to be found. Demographic studies in the wild concur. Breeding females maintain their dominance for at least 17 years (Braude personal communication) and live at least four times longer than non-breeding (»4 years) individuals (Table 1). Higher mortality rates in non-breeding castes than breeders in the wild are to be expected, given the greater likelihood of extrinsic causes of mortality by either predation or accidental death. Similar lifespan between breeders and non-breeders in captivity is all the more surprising when the energetic Table 1 Lack of diVerent MLSP among breeders and non-breeding naked mole-rats Breeder Non-breeder MLSP captivity (years) >28.3 >27 MLSP wild Braude, personal communication (years) >17 »4 45 35 Mass of old NMR >24 years (g) 123 Table 2 DiVerential reproductive success of young and old breeding females Young breeder Old breeder Mass (g) 37 45 Mean mass increase (%) 33 84 Max mass increase (%) 57 110 Mean litter size 9 16 Max litter size 12 29 Pup mass (g) 1.0–2.2 1.0–2.4 demands associated with pregnancy are taken into account (Urison and BuVenstein 1995). Breeding females may breed continuously (approximately every 3 months) from the time they become breeders until they die. Body mass may double by the end of gestation and this is associated with a >1.5-fold increase in metabolic rate (Urison and BuVenstein 1995), even higher energetic demand during lactation, and concomitant oxidative stress. Clearly breeding females partition a considerable proportion of their energy resources into reproduction, yet nevertheless adequately maintain their soma and reproductive tissues far longer than do most small mammals. Naked mole-rat reproductive data therefore does not support the disposable soma theory of aging. Fertility clearly does not become impaired with age, as commonly occurs in most mammals and as such naked mole-rat reproductive information concurs with one of the key criteria used in the deWnition of negligible senescence. Age-related changes in behavior, physiology and morphology Older naked mole-rats, like those of most other species, tend to be less active. Sleep patterns in both young and old naked mole-rats are random and do not follow a speciWc circadian rhythm, as commonly occurs in other small mammals (Davis-Walton and Sherman 1994; Riccio and Goldman 2000), but more closely resemble those of longer living species, be they aquatic or large mammals (Siegel 2005). Long-living mole-rats show only slight changes in morphology and maintain physiological function and activity well into their third decade of life. Basal metabolic rate (BMR) is unchanged and gastrointestinal absorption and enzymatic activities show only slight deterioration with age (O’Connor et al. 2002; BuVenstein 2005; Yang and BuVenstein 2002). Similarly, sustained vascular youthfulness, in keeping with attenuated rates of aging, is evident (Fig.5; Csiszar et al. 2007). Regardless of whether BMR is expressed per fat free mass or as mass-speciWc metabolic rate it remains J Comp Physiol B (2008) 178:439–445 443 120 100 80 Ma x im a l l v a s cu la r r el a x at io n to acetyl choline (%) 60 40 Rat Naked mole-rat 20 0 0 2 6 4 120 8 10 12 14 10 12 14 Age (years) 100 80 60 40 20 0 0 2 6 4 8 % of maximal lifespan Fig. 5 Unchanged age-related vascular relaxation properties in response to acetylcholine of naked mole-rat vessels, compared to those from Fisher 344 rat. Figure modiWed from Csiszar et al. (2006) unchanged at least till 20 years of age (Table 3; O’Connor et al. 2002). BMR of naked mole-rats is 30% lower than predicted by body mass (O’Connor et al. 2002), but this reduction in oxygen consumption with its inevitable byproduct, oxidative damage, is not suYcient to fully account for the Wvefold diVerence in extended longevity (compared to that predicted from body size). Given their exceptional longevity it is not surprising that naked mole-rats have the highest mass-speciWc lifetime energy expenditure (LEE) of any known mammal (O’Connor et al. 2002). LEE does not take into account the diVerences in metabolic expenditure when not at rest nor the amount of time spent active. Unchanged vascular function is also evident, with blood vessels maintaining elasticity over a prolonged period of time (Csiszar et al. 2006). Unlike the substantial decline in NO-mediated dilations in rat arteries (Hamilton et al. 2001; Table 3 Unchanged physiological, morphological and biochemical variables with age in naked mole-rats Csiszar et al. 2002, 2005), sensitivity of the naked mole-rat smooth muscle cells to NO does not change over a 10-year period or over a similar proportionate change in total lifespan (Fig. 5). Indeed NO is known to exert vasculoprotective and anti-atherogenic eVects and atherosclerotic vascular disease is often thought to be due decreased bioavailability of NO with aging (reviewed in reference Csiszar et al. (2005)) and data on naked mole-rat support this premise. Bone integrity of naked mole-rats is also maintained from 2 to more than 24 years of age, with considerable evidence of highly eYcient bone remodeling processes (large number of secondary osteons, well maintained cortical bone and remodeling through growth plate) so that bone mineral content remains unchanged (Kramer, Jepsen, Terranova and BuVenstein, unpublished data). Many animals as they age become insulin-insensitive and glucose-intolerant. Not surprisingly given the attenuated age-related physiological and morphological changes, no change in glucose handling is evident over a large age range (BuVenstein et al. 2007) and similarly glycated hemoglobin levels remain constant (Yang and BuVenstein 2004). Although the particular sets of genes responsible for senescence and the associated physiological end-points are likely to vary among species, attenuated changes in a wide variety of physiological, morphological, biochemical and molecular variables with age collectively suggest that physiological and biochemical functions of naked mole-rats are not compromised. As such, the naked mole-rat appears to meet the third criteria of negligible senescence. Age-related changes in biochemical markers One would expect that long-lived animals would accrue less oxidative damage (Harman 1956). However, recent studies revealed that this is not the case in naked mole-rats. These rodents produce similar amounts of, or marginally Naked mole-rat Mice and rats Source Basal metabolic rate Unchanged Declines O’Connor et al. (2002) Vascular relaxation Unchanged Declines Csiszar et al. (2006) Bone cortical area Unchanged Declines Kramer, unpublished data Bone mineral density Unchanged Declines O’Connor et al. (2002) Articular cartilage Unchanged Declines Pinto, unpublished data ROS production Unchanged Increases Csiszar et al. (2006) Antioxidant activity Unchanged Increases Andziak et al. (2005) Oxidative damage Unchanged Increases Andziak and BuVenstein (2006) Glucose tolerance Unchanged Declines BuVenstein et al. (2007) Glycated hemoglobin Unchanged Declines Yang and BuVenstein (2002) 123 444 less, ROS than shorter-lived species (Labinskyy et al. 2006; Lambert et al. 2007) and possess an antioxidant defense suite that is not superior to shorter living rodents with similar levels of catalase activity, low levels of glutathione and glutathione peroxidase and with no evidence of compensation by the upregulation of other antioxidants (Andziak et al. 2005, 2006). Even from young age naked mole-rats exhibit high levels of oxidative damage to DNA lipids and proteins without any impact upon physiological function (Andziak et al. 2006), yet they continue to thrive for an additional 26 years while young mice have less than 3 years of life left (Andziak et al. 2006). Despite these very high steady state oxidative damage levels, naked mole-rats exhibit markedly attenuated age-related changes in mitochondrial mass and eYciency as well ROS production (Cziszar et al. 2007), antioxidant activity (Andziak and BuVenstein 2006), membrane composition (Hulbert et al. 2006) and lipid peroxidation (Andziak and BuVenstein 2006). Moreover, although protein oxidation is high, it too does not alter with age and appears to have no impact on enzymatic activity, unfolding resistance or ubiquitination (Pierce et al. 2006). These data collectively suggest that even at the cellular level functional integrity is maintained during their long lives and repair and removal of damaged macromolecules closely match that accrued. Membrane composition and tight regulation of cellular metabolism and the functional organelles involved in these processes, may explain the remarkable resistance of naked mole-rat tissues to a wide range of oxidative insults (Labinskyy et al. 2006; Hulbert et al. 2007). It is not known why naked mole-rats exhibit such high levels of oxidative damage, especially at young age with no impairment of function. While it could be because oxidative damage has nothing to do with aging, it could also be due in part to early life stresses prior to the development of an adequate antioxidant defense, and these may be associated with being housed in captivity under the comparatively hyperoxic above ground atmosphere relative to that encountered in deep underground burrows teeming with colony members and other oxygen-sapping organisms (BuVenstein 2000). Alternately, high oxidative stress may reXect the lack of a circadian sleep rhythm and short naps rather than prolonged sleep especially in young precocial pups (Bennett and Faulks 2000). Both rodents and Xies that are sleep-deprived have high levels of oxidative stress and evidence of membrane disruption and sleep deprivation can cause death more quickly than food deprivation (Siegel 2005). High levels of oxidative stress with no impact upon longevity and physiological function and furthermore not resulting in age-related damage accrual challenge the revered oxidative stress theory of aging (Harman 1956) and thus demand further investigation. 123 J Comp Physiol B (2008) 178:439–445 Conclusion Despite some gaps in our current knowledge concerning comprehensive demographic statistics and the proximate mechanisms employed to retard aging, naked mole-rats appear to concur with all three criteria for negligible senescence proWles. Despite living nine-times longer than similar sized mice, these rodents show attenuated age-associated acceleration in mortality risk, continue to reproduce well into their third decade and show no typical signs of agerelated deteriorations in physiological or biochemical function, until possibly very near their MLSP. No doubt, these unusual rodents will provide novel insights into the mechanisms involved in aging, be they public or private (Martin 2006), thereby facilitating their extraordinary longevity. They thus may prove to be an invaluable useful non-traditional model for aging research and for testing the ubiquity of both ultimate and proximate theories of aging. Acknowledgments Peter Hornsby, Pedro de Magalhaes and an anonymous reviewer are sincerely thanked for their constructive comments on this manuscript. Author gratefully acknowledges the contributions by his CCNY students (Yael Edrey, Yael Grun Kramer, Mario Pinto and Ting Yang) and collaborators (Dianna Casper, Asish Chaudhuri Anthony Hulbert, Jenny Jarvis, Karl Jepsen, Justine Salton, Carl Terranova). The animal care staV at the University of Cape Town, Medical School of the University of the Witwatersrand, and City College of New York is sincerely thanked for their dedicated and prolonged care of these unusual colonies. 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