26

Lifespan and Aging Patterns

Elizabeth S. Russell

This chapter contains a brief presentation of knowledge up to 1964 concerning the longevity of inbred mice. Mice have long been favored subjects in investigations of the nature of aging. Much of the available information on their lifespan comes from isolated experiments each of which involved one or a very few genotypes. Some of the best material for comparison of the relative longevity of different genetic types comes from life-histories of mice of many inbred strains maintained together under a single regimen, as in the pedigreed expansion stocks of a supply colony.

The first purpose of this chapter is to provide information about lifespans of mice from a variety of inbred strains and F₁ hybrids to assist investigators in the design of experiments. Although the data summarized here provide a reliable comparison of the potentialities of many genotypes, readers who wish to put this information to practical use are cautioned against expecting exact correspondence between these data and observations in their own laboratories. In any experiment involving lifespan, concomitant controls are of course essential. The second purpose of this chapter, particularly pertinent to mouse pathology, is to present a discussion of the aging patterns of mice and of variation between genetic groups of mice in the incidence of particular pathological conditions. Many of the research uses of inbred mice have developed from the reliable and predictable development of specific types of tumors, described in detail in Chapter 27. Differences between genotypes are also known in the incidence of particular types of nonneoplastic pathological conditions. To the extent that these differences are genetically controlled, such conditions may be termed constitutional disease ( Chapter 29). In this chapter I will deal with relationships between lifespan and the incidence of pathological conditions and will discuss genetic and environmental influences on longevity of mice.

LIFESPANS OF INBRED AND F₁ HYBRID MICE

Continuity of a particular inbred strain implies that mice must live long enough to produce offspring, but beyond that minimal requirement there are great differences between strains in characteristic lifespan. Comfort ( 1959) stated that the typical "life span (reckoned as the last decile survival) ranges from 1.3 to 3 years in various strains of mice." Mice from strains with the shortest lifespans (i.e., AKR/J and C3H/J females) are usually extremely susceptible to a specific kind of neoplasm. Certain long-lived strains and F₁ hybrids have been much favored in radiation experiments. Since 1959, CBA ( Neary, 1960; Comfort, 1959; Alexander and Connell, 1960, 1963), C3HeB ( Comfort, 1959; Grahn and Hamilton, 1964), RF and RFM ( Upton, 1960; Storer, 1962; Spalding and Strang, 1962), A ( Duhig and Warren, 1960), LAF₁ ( Upton et al., 1960; Upton, 1960; Neary, 1960; Lesher et al., 1960; Cole et al., 1960; Sacher and Grahn, 1964), (101 x C3H)F₁ ( Cosgrove et al., 1964), and noninbred CF#1 ( Finkel et al., 1959; Curtis and Gebhard, 1959) have been so used. Mean lifespans reported for nonbred controls in these radiation experiments ranged from 460 days (strain A females, Duhig and Warren, 1960) to 866 days (CBA females, Neary et al., 1962), with some difference between means for the same strain in different laboratories. In many of these control groups, the oldest survivors lived more than 1,000 days. Differences in lifespan have been found between lines of mice selected for large and small body size, with large mice surviving longer in one experiment ( Chai, 1959), and selected small mice in another ( Roberts, 1961). Incrosses between these selected lines, as in all hybrid crosses which have been reported, F₁ hybrid offspring survived significantly longer than did mice of either parental type. However, one male in a line (NS) selected for low body weight survived 1330 days, which possibly is the longest recorded lifespan for the laboratory mouse ( Roberts, 1961). A detailed study of the effects of dietary differences on lifespans of mice gives comparative data on nonbred C57BL/6J, A/J, and DBA/2J (Silberberg et al., 1961, 1962a, 1962b). Similarly, Mühlbock's ( 1959) study of factors influencing lifespan of inbred mice gives comparative data for DBA_f, O2o, CBA, C3H, and C3H_f, and Murray's ( 1965) analysis of factors influencing rate of mammary tumor incidence gives comparative data for C3H, C3HeB, DBA, A, and MA/My.

Data collected at The Jackson Laboratory provide a basis for comparing larger numbers of inbred strains and F₁ hybrids. This material, previously unpublished, may be suitable for demonstrating: (1) range of lifespans characteristic of mice in single genetically homogeneous populations, (2) differences between inbred strains in means and range of lifespan, (3) effects of sex, breeding, environmental conditions, and hybrid vigor on lifespan.

Pedigreed expansion stocks

Large colonies of mice from many different inbred strains, all descended from mice in the Foundation Stocks of The Jackson Laboratory, are maintained on a common regimen in the Pedigreed Expansion Stocks (PES) of The Jackson Laboratory ( Green, 1964). Inbred but nonpedigreed offspring of PES mice constitute the Production Stocks (PS) of The Jackson Laboratory. In order to provide data for comparison of the characteristics of mice from 16 different inbred strains, total lifespans were determined for all breeding females and a great majority of the males used as breeders during the first 5 years of the PES colony from 1948 to 1952, plus a representative sample of breeders used from 1952 to 1956. In the sense of uniformity of timespan, place, and most of the environmental conditions, the mice belonged to a single population, but genetically they consisted of 16 different subpopulations of varying sizes. All mice were fed Purina Fox Chow or Purina Lab Chow, kept in wooden boxes until 11 months of age, and the retired in groups of two to five. Males killed by fighting shortly after retirement have been eliminated from the data. The physical condition of all mice was checked at least once per week for their entire lifetime; the majority of the animals were killed and autopsied when moribund; time of death was recorded for the remainder.

The mean lifespans ( Table 26-1, columns 1, 3) and curves for per cent survival (Figures 26-1, 26-2) varied considerably among the component inbred strains. In AKR/J, all were dead by 550 days; in C57BL/6J, the mean longevity of females was 561 days, that of males 539 days. Losses prior to 300 days were restricted almost exclusively to males and females of the AKR/J and to females of the C3H/J inbred strains. Between 300 and 649 days. there were many deaths in all strains (except those mentioned above), but there were still significant differences between strains in mean lifespan. Beyond 650 days, the proportion remaining alive was less than 20 per cent in all strains except the three related ones C57BL/6J, C57L/J, and C57BR/cdJ, and no mice survived beyond 925 days. From 1952 to 1957, lifespans of virgin females of these same inbred strains in the PES were determined ( Table 26-1, column 2). For 14 of the 15 tested strains, virgins survived significantly longer than did their bred sisters. Only in C57BL/6J did as many as one-half of the mice live more than 650 days ( Figure 26-3).

Following transfer of the Pedigreed Expansion Stocks in 1959 to new improved quarters, with change in diet, housing, cleanliness, and pathogen control, significantly increased lifespans were observed in all of the seven inbred strains for which more than 50 new life-histories of bred females were followed ( Table 26-1, column 4). Animals were maintained Salmonella-free and housed as single pairs in stainless-steel pens until retired at 8 to 10 months of age. They were fed Old Guilford pellets (11 per cent fat, 19 per cent protein). Observation regimen was the same as in the original study. In each case increased longevity was observed, associated with delay in onset of mortality, with no increase in maximum lifespan. Fifty-five per cent of the C57BL/6J bred females survived more than 650 days ( Figure 26-1).

Hybrid mice from production stocks

F₁ hybrid mice from crosses between two inbred strains, combining genetic homogeneity with hybrid vigor, are favored animals for many types of research which do not require production of genetically homogeneous offspring. To provide information on characteristics of six different types of F₁ hybrids, total lifespans were determined for virgin animals born in the Production Stocks (PS) between 1954 and 1958, maintained in groups of five sex-linked animals per pen, and observed according to the PES regimen ( Table 26-2). For each F₁ hybrid, the survival curves of males ( Figure 26-4) and of virgin females were very similar, and the mean and maximum lifespans exceeded those for males and virgin females of either parent strain. In five of the six F₁ hybrids, more than half of the mice of both sexes lived more than 650 days.

CHARACTERISTIC AUTOPSY FINDINGS

When inbred mice are autopsied at advanced ages, the incidence of specific pathological lesions varies according to strain, sex, and breeding history (Dunn, 1954a, 1954b; Hoag, 1963; Chapters 20, 27, 29). The official listing of inbred strains of mice ( Staats, 1964) gives information on characteristic tumor incidences for many inbred strains and sublines. Incidences observed for different colonies of the same inbred strain tend to be very similar, but significant differences have been noted ( Law et al., 1955; Hoag, 1963). The longevity studies of bred animals from PES of The Jackson Laboratory provide good material for comparison of the aging patterns of mice from many different inbred strains, since a large proportion of these mice were autopsied when moribund, with abnormal-appearing tissues diagnosed by a pathologist (E.A. Fekete, P. Borges, or E.D. Murphy of The Jackson Laboratory staff). All strain differences reported here were derived from comparisons of animals dying within the same age interval. The marked differences in pathological findings between strains compared at equivalent ages demonstrate a genetic contribution to the causation of many disease processes. High percentages of mammary tumors were observed in C3H/J, A/HeJ, DBA/1J, and DBA/2J females, plus a moderate number in A/J females, in contrast to low percentages in all other strains. In all of these high mammary tumor strains, time of appearance of mammary tumors (influenced by genes, mammary tumor inciter, and hormonal stimulation) was the major determinant of female lifespan ( Hummel and Little, 1963; Mühlbock, 1959; Murray, 1965; Pilgrim and Dowd, 1963). C3H/J females showed the greatest susceptibility to mammary cancer (95 to 99 per cent of all deaths), with a highly significant tendency to die extremely early. Incidence of reticular neoplasia differed greatly among the 10 tested inbred strains. The incidence of lymphatic leukemia was significantly higher (P › 0.0001) and time of appearance earlier in the AKR/J than in all other strains observed; because of the early onset, there is little doubt that this is a specific AKR/J characteristic. A low incidence of reticular neoplasia was also observed in very old mice of several inbred strains, and the question arose as to whether this was a nonspecific result of the aging process. This is particularly pertinent because the incidence was highest in C57BL/6, which had the largest proportion of long survivors. However, proof of genetic contribution to the causation of late-appearing neoplasms of reticular tissue was provided by analysis of frequencies in the late general death period. C57BL/6J mice of both sexes dying between 450 and 649 days showed a significantly higher (P › 0.001) incidence of reticular neoplasia (frequently reticulum cell sarcoma) than did mice of all other inbred strains dying in the same age interval.

The appearance of primary lung tumors was also restricted to a small number of inbred strains. The incidence was especially high (23 to 59 per cent) in A/HeJ and A/J mice of both sexes. Statistical analysis demonstrated that at each age interval these mice were significantly more susceptible to lung tumors than were mice of all other inbred strains observed. The incidence of lung tumors increased slightly with advancing age in A/HeJ males. The lower incidence observed in A/HeJ females almost certainly resulted from early mammary tumor deaths among these females. Arrangement of autopsy records by age groups disclosed an age-dependent susceptibility to primary lung tumors in BALB/c mice of both sexes. Before 450 days these mice showed a low incidence of lung tumors (10 to 13 per cent), but the frequency increased markedly in later autopsies (34 to 45 per cent). Between 450 and 649 days BALB/c mice, though having significantly fewer lung tumors than mice of either A strain, still had a significantly higher incidence than was observed in the combined populations of the other seven inbred strains.

Hepatomas were observed only in the older mice and were limited almost entirely to males. Among mice autopsied between 450 and 649 days, the incidence of hepatoma was high in C3H, C57BR/cd, and C57L males. The incidence was significantly higher in C3H than in the other two susceptible strains, whose incidence was, in turn, significantly greater than that in the other seven strains observed.

Certain nonneoplastic lesions also appeared to be restricted to particular inbred strains. Calcified areas on the heart were frequently observed in DBA/2 and C3H females, very rarely in other mice. Mice of the A/HeJ and A/J strains showed high incidence of papillonephritis, increasing with advancing age to nearly 100 per cent. This condition is believed to be related to amyloidosis, also characteristic of these strains ( Dunn, 1954b; West and Murphy, 1965). Kidney lesions were also observed frequently in C57BL/6, C57BR/cd, and C57L mice, increasing with advancing age so that approximately 50 per cent of animals over 450 days were affected.

Aging C57BL/6 mice show hematological changes with gradual decrease in the number of erythrocytes and consequent drop in the ratio of red-cell mass to total blood volume ( Ewing and Tauber, 1964). This effect of age on blood values is probably not limited to this strain. Decline in erythrocyte number apparently does not have a strong direct effect on lifespan, since the same type of change was observed in short-lived and long-lived individuals.

ENVIRONMENTAL INFLUENCES

Broad distributions of age at death within inbred strains and differences in mean survival of mice from the same inbred strains under altered conditions demonstrate that environmental factors have significant effects on longevity. Intercurrent infections, parasitism, fighting, and occasional malocclusion account for sporadic deaths. Three specific nongenetic factors (mammary tumor virus, breeding history, and diet) affecting lifespan have been identified in controlled experiments. Individual variations in these factors may contribute to observed differences in lifespan within a single colony of a particular inbred strain. Other identifiable within-strain life-history variables, such as season of birth, age of parents at birth, or lifespan of parents, have no discernable effects upon mouse lifespan (Schlager, 1965, personal communication).

Effects on mean lifespan of certain identifiable variables have been demonstrated in a few carefully controlled experiments. High-fat diets throughout life shorten the lifespan of C57BL/6J, DBA/2J, and YBR mice ( Silberberg and Silberberg, 1954; Silberberg et al., 1955). Caloric restriction lowered the mean lifespan of C57BL/6J, A/J, and DBA/2 mice by increasing juvenile mortality, whereas lard-enriched diets during growth increased the mean lifespans of C57BL/6 males and DBA/2 females, but not of other groups (Silberberg et al., 1961, 1962a, 1962b). Genetically obese ( ob/ ob) mice fed ad libitum had shorter lifespans than normal littermates, but restricting their food intake cancelled the difference in survival ( Lane and Dickie, 1958). Dystrophic mice have been shown to survive longer on a good than on a poor laboratory diet ( Coleman and West, 1961). Crowding has been shown to reduce mean lifespan of C3H_f mice ( Mühlbock, 1959), and type of cage to influence both lifespan and, secondarily, tumor incidence in CF#1 mice ( Finkel and Scribner, 1955). The frequently observed differences in mean lifespan between breeding and virgin females indicate that producing and rearing offspring reduces life expectancy. Forced breeding, with reduced intervals between successive litters, accentuates this life-shortening effect ( Mühlbock, 1959; Murray, 1965). Lifespan differences attributable to breeding history are particularly noticeable in strains with a high susceptibility to mammary tumors. In these strains the presence of the tumor-inducing virus greatly decreases lifespan of females ( Hummel and Littel, 1963; Murray, 1965). Evidence of this is also seen in the data given earlier in this chapter in the difference in mean lifespan between C3H/HeJ (carrying the virus) and C3HeB/J (virus-free) females. The extreme increase in mean lifespan of DBA/2J females between 1956 and 1960 can also be explained in part by loss of the mammary tumor virus during the intervening period ( Hoag, 1963).

GENETIC INFLUENCES

Considerable variations in lifespan have been observed in mice, both within and between genetically homogeneous groups. The differences observed between mice of the same inbred strain in the Pedigreed Expansion Stocks cannot be attributed to residual variability within the strain for genes affecting lifespan, since there was no correlation between lifespan of parent and of progeny (Schlager, 1965, personal communication). However the variations in means and distributions of lifespan between inbred strains of mice, each representing the replication of the same or nearly the same homozygous genotype, provide valuable material for the detection of polygenic influences on lifespan and for the identification of certain environmental factors with significant effects on longevity. The highly significant differences in lifespan observed when mice from many inbred strains are maintained together under a common regimen clearly demonstrate a large genetic contribution to the determination of total lifespan, but give no indication of the number or nature of the effective genes. Comparisons of mean lifespans and mean litter sizes of productive breeding females in 12 inbred strains showed highly significant correlations, indicating that the genetic factors which favor longevity also lead to increased fertility ( Roderick and Storer, 1961). Differences between inbred strains in aging pattern or incidence of particular pathological lesions indicate differences between strains in tissues susceptible to early degeneration. The uniform observation that F₁ hybrid animals survive longer than those of either parental inbred strain indicates that the inbred strains are homozygous for different recessive genes which affect lifespan. Further analysis of the formal genetics of aging would be very difficult. The few studies known are limited to demonstration of effects of certain deleterious genes such as lethal yellow ( A^y) ( Silberberg et al., 1955; Heston and Vlahakis, 1963; Hrubant, 1964), the viable black-and-tan allele ( a^t) ( Hrubant, 1964), obese ( ob/ ob) ( Lane and Dickie, 1958), and dystrophia muscularis ( dy/ dy) ( Coleman and West, 1961). In genetically controlled stocks where these specific mutant genes are maintained congenic with particular inbred strains, the lifespans of mice carrying mutant alleles were significantly shorter than those of homozygous normal littermates.

SUMMARY

Information on lifespans of mice from numerous inbred strains and hybrids at The Jackson Laboratory has been presented. These data reveal highly significant strain and sex differences and longer lives for virgin than for bred females. Under comparable environmental conditions the mean and maximum lifespans of F₁ hybrid mice always exceeded those observed for either parental strain. The incidence of certain kinds of neoplasia, including mammary gland tumors, reticular neoplasia, primary lung tumors, and hepatomas, differed markedly from strain to strain.

Differences between strains demonstrated the importance of genetic factors in determination of lifespan. Life-shortening effects have also been demonstrated for four specific mutant genes. Broad distribution within strains of age at death showed that environmental factors influence lifespan. Improvement of husbandry conditions increased the mean lifespans of mice from many inbred strains in the PES stocks of The Jackson Laboratory. Significant effects have been demonstrated for diet, crowding, differences in breeding history, and presence vs. absence of the mammary tumor virus.

In the design of experiments involving lifespan determination or in other studies involving old mice, both environmental and genetic controls are important. The investigator should be aware of strain differences in total lifespan and in aging pattern and should select mice of appropriate genotypes. However, because of effects of environmental variables, it is important that concomitant controls be included in all studies.

¹The preparation of this chapter and the collection of much of the information reported have been supported in part by Public Health Service Grant CA 01074 from the National Cancer Institute.

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