Aging in inbred strains of mice: study design and interim report on median lifespans and circulating IGF1 levels

Abstract

SummaryTo better characterize aging in mice, the Jackson Aging Center carried out a lifespan study of 31 geneticallydiverse inbred mouse strains housed in a specific pathogen-free facility. Clinical assessments were carried out every 6 months, measuring multiple age-related phenotypes including neuromuscular, kidney and heart function, body composition, bone density, hematology, hormonal levels, and immune system parameters. In a concurrent cross-sectional study of the same 31 strains at 6, 12, and 20 months, more invasive measurements were carried out followed by necropsy to assess apoptosis, DNA repair, chromosome fragility, and histopathology. In this report, which is the initial paper of a series, the study design, median lifespans, and circulating insulinlike growth factor 1 (IGF1) levels at 6, 12, and 18 months are described for the first cohort of 32 females and 32 males of each strain. Survival curves varied dramatically among strains with the median lifespans ranging from 251 to 964 days. Plasma IGF1 levels, which also varied considerably at each time point, showed an inverse correlation with a median lifespan at 6 months (R = )0.33, P = 0.01). This correlation became stronger if the shortlived strains with a median lifespan < 600 days were removed from the analysis (R = )0.53, P < 0.01). These results support the hypothesis that the IGF1 pathway plays a key role in regulating longevity in mice and indicates that common genetic mechanisms may exist for regulating IGF1 levels and lifespan.

Inflammation and mortality in a frail mouse model

“…In contrast, GH transgenic mice have elevated IGF-1 signaling and a significantly reduced lifespan of ∼50% compared to control strains ). This inverse correlation between median lifespan and plasma IGF-1 at 6, 12, and 18 months of age has been validated in 31 inbred mouse strains in the Aging Phenome Project (Yuan et al 2009). In the current study, the IL-10 tm/tm mice had higher serum IGF-1 levels by regression analyses and most notably at midlife; however, these mice had shorter lifespan than B6 controls.…”

“…This provides another potential clue to the premature mortality observed in these mice. Prior studies have cited high rates of IGF-1 in midlife as strong correlates of earlier mortality (Yuan et al 2009). IGF-1 is a circulating hormone of the somatotropic axis (growth hormone (GH)-IGF-1) that increases protein synthesis, accelerates cell cycle, and blocks initiation of apoptosis (Mourkioti and Rosenthal 2005).…”

Long-term α1B-adrenergic receptor activation shortens lifespan, while α1A-adrenergic receptor stimulation prolongs lifespan in association with decreased cancer incidence

“…The median age of C57BL/6 mice varies depending upon the environment but ranges from 682 to 930 days (Ikeno et al 2005;Selman and Withers 2011;reviewed in Nadon et al 2008). In a study of 31 inbred strains at Jackson Labs, C57BL/6J mice had median ages of 866 days for males and 901 days for females (Yuan et al 2009). In the same study, CBA/J mice had median ages of 679 days for males and 644 days for females.…”

“…All staff members who observed and handled the mice were trained to detect and record signs of illness and notified the veterinarian and research team immediately regarding sick animals. The veterinarian and researchers examined the mice for severity of illness or impairment, and animals were euthanized if they were not likely to survive for another 48 h. The likelihood of survival was based on the occurrence of at least two of the following clinical signs set forth by The Jackson Laboratory (Yuan et al 2009). The signs included failure to drink or eat, extreme weight loss over a short period of time, severe weakness based on responsiveness to touch, serious locomotor impairments, or tumors that had ulcerated or were bleeding (Ray et al 2010).…”

Sex differences in aging, life span and spontaneous tumorigenesis in 129/Sv mice neonatally exposed to metformin

“…Growth rate and adult body size, key markers of GH and IGF-1 actions, as well as plasma IGF-1 levels are negatively correlated with lifespan in comparisons with mice from different stocks or inbred strains, as well as with individual animals from a genetically heterogeneous population. 2,3 However, even with this evidence it may be difficult to envisage how physiological effects of hormones within normal ranges of their concentration can be detrimental for something as fundamental as longevity. The most likely explanation for this paradox can be found in the concept of antagonistic pleiotropy which emerged from analysis of genetic control of aging.…”