Pathobiology of Aging Mice and GEM

Brayton, Cory; Treuting, Piper M.; Ward, Jerrold M.

doi:10.1177/0300985811430696

Cited by 147 publications

(75 citation statements)

References 214 publications

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“…Although subordinate mice presented an earlier onset of tumors macroscopically detectable at autopsy, their incidence or spectrum was not different between the two groups, thus excluding solid tumors as a factor explaining the detrimental effect of achieved subordinate status on survival (Figure 4a,b; Figures S2 and S3a–c). Similarly, the analysis of sternum specimens, known to harbor most of the pathologies recognized as cause of death in C57BL/6J male mice (Brayton, Treuting & Ward, 2012), did not return any leukemia‐associated sign (Figure S3d–f), which was therefore discarded as a prominent cause of status‐dependent difference in survival.…”

Section: Resultsmentioning

confidence: 96%

Social stress shortens lifespan in mice

et al. 2018

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SummaryStress and low socioeconomic status in humans confer increased vulnerability to morbidity and mortality. However, this association is not mechanistically understood nor has its causation been explored in animal models thus far. Recently, cellular senescence has been suggested as a potential mechanism linking lifelong stress to age‐related diseases and shorter life expectancy in humans. Here, we established a causal role for lifelong social stress on shortening lifespan and increasing the risk of cardiovascular disease in mice. Specifically, we developed a lifelong chronic psychosocial stress model in which male mouse aggressive behavior is used to study the impact of negative social confrontations on healthspan and lifespan. C57BL/6J mice identified through unbiased cluster analysis for receiving high while exhibiting low aggression, or identified as subordinate based on an ethologic criterion, had lower median and maximal lifespan, and developed earlier onset of several organ pathologies in the presence of a cellular senescence signature. Critically, subordinate mice developed spontaneous early‐stage atherosclerotic lesions of the aortic sinuses characterized by significant immune cells infiltration and sporadic rupture and calcification, none of which was found in dominant subjects. In conclusion, we present here the first rodent model to study and mechanistically dissect the impact of chronic stress on lifespan and disease of aging. These data highlight a conserved role for social stress and low social status on shortening lifespan and increasing the risk of cardiovascular disease in mammals and identify a potential mechanistic link for this complex phenomenon.

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Section: Resultsmentioning

confidence: 96%

Social stress shortens lifespan in mice

et al. 2018

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“…We note few systematic patterns as follows, in the body composition, leucocyte and blood chemistry data. AKR/J mice show faster downtrends in terms of body mass index (and some related measurements with negligible longitudinal trends), possibly due to the thymic lymphoma they develop by 18 M of age (Storer, 1966; Brayton et al ., 2012). Regarding the leucocyte data, males of the SJL/J strain are singled out by enrichment in opposite trends.…”

Section: Resultsmentioning

confidence: 99%

Inbred mouse strains reveal biomarkers that are pro‐longevity, antilongevity or role switching

et al. 2014

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Traditionally, biomarkers of aging are classified as either pro-longevity or antilongevity. Using longitudinal data sets from the large-scale inbred mouse strain study at the Jackson Laboratory Nathan Shock Center, we describe a protocol to identify two kinds of biomarkers: those with prognostic implication for lifespan and those with longitudinal evidence. Our protocol also identifies biomarkers for which, at first sight, there is conflicting evidence. Conflict resolution is possible by postulating a role switch. In these cases, high biomarker values are, for example, antilongevity in early life and pro-longevity in later life. Role-switching biomarkers correspond to features that must, for example, be minimized early, but maximized later, for optimal longevity. The clear-cut pro-longevity biomarkers we found reflect anti-inflammatory, anti-immunosenescent or anti-anaemic mechanisms, whereas clear-cut antilongevity biomarkers reflect inflammatory mechanisms. Many highly significant blood biomarkers relate to immune system features, indicating a shift from adaptive to innate processes, whereas most role-switching biomarkers relate to blood serum features and whole-body phenotypes. Our biomarker classification approach is applicable to any combination of longitudinal studies with life expectancy data, and it provides insights beyond a simplified scheme of biomarkers for long or short lifespan.

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“…Although most of these signs can occur in all aging mouse strains, our study specifically evaluated aging C57BL/6J mice. Other mouse strains may exhibit characteristic diseases and signs of clinical deterioration (60), and these could be used to tailor the frailty index to particular mouse strains. It also is possible that this general approach for creating a frailty index has more widespread applicability.…”

Section: Discussionmentioning

confidence: 99%

A Clinical Frailty Index in Aging Mice: Comparisons With Frailty Index Data in Humans

Whitehead¹,

Hildebrand

Sun³

et al. 2013

The Journals of Gerontology: Series A

362

423

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We previously quantified frailty in aged mice with frailty index (FI) that used specialized equipment to measure health parameters. Here we developed a simplified, noninvasive method to quantify frailty through clinical assessment of C57BL/6J mice (5–28 months) and compared the relationship between FI scores and age in mice and humans. FIs calculated with the original performance-based eight-item FI increased from 0.06±0.01 at 5 months to 0.36±0.06 at 19 months and 0.38±0.04 at 28 months (n = 14). By contrast, the increase was graded with a 31-item clinical FI (0.02±0.005 at 5 months; 0.12±0.008 at 19 months; 0.33±0.02 at 28 months; n = 14). FI scores calculated from 70 self-report items from the first wave of the Survey of Health, Ageing and Retirement in Europe were plotted as function of age (n = 30,025 people). The exponential relationship between FI scores and age (normalized to 90% mortality) was similar in mice and humans for the clinical FI but not the eight-item FI. This noninvasive FI based on clinical measures can be used in longitudinal studies to quantify frailty in mice. Unlike the performance-based eight-item mouse FI, the clinical FI exhibits key features of the FI established for use in humans.

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Pathobiology of Aging Mice and GEM

Cited by 147 publications

References 214 publications

Social stress shortens lifespan in mice

Social stress shortens lifespan in mice

Inbred mouse strains reveal biomarkers that are pro‐longevity, antilongevity or role switching

A Clinical Frailty Index in Aging Mice: Comparisons With Frailty Index Data in Humans

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