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. 2024 Oct;46(5):4203-4215.
doi: 10.1007/s11357-024-01200-5. Epub 2024 May 17.

Quantification of healthspan in aging mice: introducing FAMY and GRAIL

Dudley W Lamming  1
Affiliations

Quantification of healthspan in aging mice: introducing FAMY and GRAIL

Dudley W Lamming. Geroscience. 2024 Oct.

Abstract

The population around the world is graying, and as many of these individuals will spend years suffering from the burdens of age associated diseases, understanding how to increase healthspan, defined as the period of life free from disease and disability, is an urgent priority of geroscience research. The lack of agreed-upon quantitative metrics for measuring healthspan in aging mice has slowed progress in identifying interventions that do not simply increase lifespan, but also healthspan. Here, we define FAMY (Frailty-Adjusted Mouse Years) and GRAIL (Gauging Robust Aging when Increasing Lifespan) as new summary statistics for quantifying healthspan in mice. FAMY integrates lifespan data with longitudinal measurements of a widely utilized clinical frailty index, while GRAIL incorporates these measures and also adds information from widely utilized healthspan assays and the hallmarks of aging. Both metrics are conceptually similar to quality-adjusted life years (QALY), a widely utilized measure of disease burden in humans, and can be readily calculated from data acquired during longitudinal and cross-sectional studies of mouse aging. We find that interventions generally thought to promote health, including calorie restriction, robustly improve healthspan as measured by FAMY and GRAIL. Finally, we show that the use of GRAIL provides new insights, and identify dietary restriction of protein or isoleucine as interventions that robustly promote healthspan but not longevity in female HET3 mice. We suggest that the routine integration of these measures into studies of aging in mice will allow the identification and development of interventions that promote healthy aging even in the absence of increased lifespan.

Keywords: Calorie restriction; Frailty; Healthspan; Isoleucine restriction; Lifespan.

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Conflict of interest statement

DWL has received funding from, and is a scientific advisory board member of, Aeovian Pharmaceuticals, which seeks to develop novel, selective mTOR inhibitors for the treatment of various diseases.

Figures

Fig. 1
Fig. 1
The Frailty-Adjusted Mouse Year (FAMY) as a measure of mouse healthspan. A–B Survival (A) and frailty index (B) of C57BL/6J.Nia male mice from [9]. C Illustration of FAMY calculation. The FAMY score for an individual mouse combines the area under the curve of 1-frailty of an individual animal, which varies over time; 1-FI is set to 1.0 at t = 0, and to 0.3 at the day of death. D Frailty-Adjusted Mouse Years (FAMY) in years was calculated using the survival and frailty data plotted in panels A and B. Max FAMY (theoretical) indicates the FAMY score if the longest-lived mouse in this study remained in perfect health (FI = 0) for its entire life. E FAMY plotted as function of lifespan. The best-fit linear regression line with 95% confidence bands is shown. A–B, D–E n = 60 biologically independent mice
Fig. 2
Fig. 2
Quantifying the effect of CR on the healthspan of inbred mice with FAMY. A–B Survival (A) and frailty index (B) of C57BL/6J male mice fed either ad libitum or calorie restricted (CR) starting at 10 weeks of age. C–D Survival (C) and frailty index (D) of C57BL/6J female mice fed either AL or CR starting at 10 weeks of age. E FAMY calculated using the survival and frailty data plotted in panels A–D. F FAMY plotted as function of lifespan. A, C Log-rank test for AL vs. CR. B, D Mixed-effects model (REML) for time and diet with post hoc Sidak’s test, *p < 0.05. E Sidak test following 2-way ANOVA. *p < 0.05, p-values for the overall effect of diet, sex, and the interaction represent the significant p-values from the two-way ANOVA. F The best-fit linear regression line for each group is shown. A–F n = 32 AL males, 19 CR males, 27 AL females, 20 CR females. Data represented as mean ± SEM
Fig. 3
Fig. 3
CR, but not fasting, improves the healthspan of Diversity Outbred mice. A Healthspan (FAMY) of female DO mice fed the indicated diets from 2.5 years of age were plotted and calculated using the surivial and frailty data from Luciano et al., 2024 [24]. B Healthspan (FAMY) of female DO mice fed the indicated diets from 6 months of age was calculated during the surivial and frailty data from Di Francesco et al., 2023 [25]
Fig. 4
Fig. 4
Quantifying the effect of reduced protein or isoleucine on the healthspan of genetically heterogeneous mice with FAMY. A–B Survival of male (A) and female (B) UM-HET3 mice fed the indicated diets starting at 6 months of age. C–D Frailty index of the mice plotted in panels A–B. E FAMY calculated using the survival and frailty data plotted in panels A-D. A–B Log-rank test for control vs. IleR. C–D Mixed-effects model (REML) for time and diet with post hoc Tukey’s test, *p < 0.05 control vs. PR and control vs. IleR; #p < 0.05 control vs. IleR only. E Tukey test following 2-way ANOVA. *p < 0.05, p-values for the overall effect of diet, sex, and the interaction represent the significant p-values from the two-way ANOVA. A–E n = 29 control male, 33 PR male, 29 IleR male; 31 Control female, 28 PR female, 29 IleR female. Data represented as mean ± SEM
Fig. 5
Fig. 5
Integrating frailty, healthspan assays, and the hallmarks of aging with GRAIL (Gauging Robust Aging when Increasing Lifespan). A Illustration of GRAIL calculation. The GRAIL score for an individual mouse combines the area under the curve of 1-frailty of an individual animal (GRAIL-FI), which varies over time, and information about the average effect on healthspan assays and the hallmarks of aging (GRAIL-HH). B GRAIL calculated using the survival and frailty data plotted in Fig. 3A–D. Tukey test following 2-way ANOVA. *p < 0.05, p-values for the overall effect of diet, sex, and the interaction represent the significant p-values from the two-way ANOVA. n = 29 control male, 33 PR male, 29 IleR male; 31 control female, 28 PR female, 29 IleR female. Data represented as mean ± SEM
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