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Fat maintenance is a predictor of the murine lifespan response to dietary restriction
Open accessAbstract
Summary: Dietary restriction (DR), one of the most robust life‐extending manipulations, is usually associated with reduced adiposity. This reduction is hypothesized to be important in the life‐extending effect of DR, because excess adiposity is associated with metabolic and age‐related disease. Previously, we described remarkable variation in the lifespan response of 41 recombinant inbred strains of mice to DR, ranging from life extension to life shortening. Here, we used this variation to determine the relationship of lifespan modulation under DR to fat loss. Across strains, DR life extension correlated inversely with fat reduction, measured at midlife (males, r = −0.41, P < 0.05, n = 38 strains; females, r = −0.63, P < 0.001, n = 33 strains) and later ages. Thus, strains with the least reduction in fat were more likely to show life extension, and those with the greatest reduction were more likely to have shortened lifespan. We identified two significant quantitative trait loci (QTLs) affecting fat mass under DR in males but none for lifespan, precluding the confirmation of these loci as coordinate modulators of adiposity and longevity. Our data also provide evidence for a QTL previously shown to affect fuel efficiency under DR. In summary, the data do not support an important role for fat reduction in life extension by DR. They suggest instead that factors associated with maintaining adiposity are important for survival and life extension under DR.
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“sEV-Ys induced a slight increase in brown interscapular adipose tissue mass (Figures S5D and S5E), which has been previously linked to increased lifespan (Liao et al., 2011)”
From Small Extracellular Vesicles Have GST Activity and Ameliorate Senescence-Related Tissue Damage (2020) · cites this paper as Liao et al., 2011
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“Subsequent studies in the ILS/ISS strains have since suggested a correlation between the response to CR and the ability of mice to increase or maintain fat mass while on a CR regimen [33].”
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“In addition, the finding that mice with a higher fat content live longer (Liao et al., 2011) provides evidence that fat plays an important role in lifespan regulation.”
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“When 41 recombinant inbred strains of mice, were exposed to lifelong 40% CR, a reversed correlation was observed between fat reduction and CR-increased lifespan (19,20).”
MethodObesity, Metabolism, and Aging: A Multiscalar Approach
Bentley, R. A., Ross, C. N., & O’Brien, M. J. (2018) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2017.11.016 · Cited by 22
Aging and energetics’ ‘Top 40’ future research opportunities 2010-2013
Allison, D. B., Antoine, L. H., Ballinger, S. W., Bamman, M. M., Biga, P. R., Darley-Usmar, V. M., Fisher, G., Gohlke, J. M., Halade, G. V., Hartman, J. L., et al. (2014) · F1000Research · doi:10.12688/f1000research.5212.1 · Cited by 21
“These included: (1) Calorie restriction (CR) longevity response, (2) role of mTOR (mechanistic target of Rapamycin) and related factors in lifespan extension, (3) nutrient effects beyond energy (especially resveratrol, omega-3 fatty acids, and selected amino acids), 4) autophagy and increased longevity and health, (5)…”
BackgroundThe road ahead of dietary restriction on anti-aging: focusing on personalized nutrition
Duan, H., Li, J., Yu, L., & Fan, L. (2022) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2022.2110034 · Cited by 20
“For example, Liao et al. demonstrated that the mice with a minimum reduction in fat under CR were more likely to live longer (Liao et al. 2011).”
BackgroundCaloric Restriction Paradoxically Increases Adiposity in Mice With Genetically Reduced Insulin
Dionne, D. A., Skovsø, S., Templeman, N. M., Clee, S. M., & Johnson, J. D. (2016) · Endocrinology · doi:10.1210/en.2016-1102 · Cited by 19
Díaz‐Ruiz, A., Francesco, A. D., Carboneau, L., Levan, S., Pearson, K. J., Price, N. L., Ward, T. M., Bernier, M., de Cabo, R., & Mercken, E. M. (2018) · The Journals of Gerontology Series A · doi:10.1093/gerona/gly112 · Cited by 17
Genetics of metabolic syndrome: potential clues from wild-derived inbred mouse strains
Karunakaran, S., & Clee, S. M. (2017) · Physiological Genomics · doi:10.1152/physiolgenomics.00059.2017 · Cited by 17
“Examples of such MetS-related phenotypes that have been studied in mice include maternal genetic effects on offspring adiposity (17), the browning of white adipose tissue (83), response to exercise (82), response (even of the microbiome) to dietary interventions (91, 114, 155), regulation of pancreatic islet gene expr…”
BackgroundRodent diet aids and the fallacy of caloric restriction
Wolf, A. M. (2021) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2021.111584 · Cited by 15
“Beyond middle age however, the capacity to maintain body weight becomes a predictor of life span, and the negative correlation between body weight and life span disappears (Liao et al., 2011).”
Adaptations to chronic rapamycin in mice
Dodds, S. G., Livi, C. B., Parihar, M., Hsu, H.-K., Benavides, A. D., Morris, J., Javors, M. A., Strong, R., Christy, B. A., Hasty, P., et al. (2016) · Pathobiology of Aging & Age-related Diseases · doi:10.3402/pba.v6.31688 · Cited by 15
“We also analyzed fat since we previously showed its responsiveness to chronic eRapa (3), and because of the important role it plays in nutrient homeostasis and energy balance (31) and in aging (32).”
BackgroundWilkie, S. E., Mulvey, L., Sands, W. A., Marcu, D. E., Carter, R. N., Morton, N. M., Hine, C., Mitchell, J. R., & Selman, C. (2020) · GeroScience · doi:10.1007/s11357-020-00168-2 · Cited by 15
“…strain-specificity in longevity following 40% DR (Liao et al. 2010; Rikke et al. 2010), and phenotypic parameters linked to the ageing process, such as in mitochondrial function and adiposity, have been shown to differ between ILSXISS strains under 40% DR (Liao et al. 2011; Mulvey et al. 2016).”
BackgroundInfluentialGhimire, S., & Kim, M. S. (2015) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2015/813801 · Cited by 12
“This is shown in a study on rodents that found a correlation between maintaining adipose levels and lifespan extension under DR [27].”
BackgroundSwindell, W. R., List, E. O., Berryman, D. E., & Kopchick, J. J. (2018) · Aging · doi:10.18632/aging.101424 · Cited by 13
“The C57BL/6 strain, for example, appears to retain fat mass with aging better than DBA/2 mice [26], and along the same lines recombinant inbred strains responding favorably to CR are better able to maintain adiposity compared to those strains with lifespan shortening due to CR [25].”
BackgroundLongevity. The allostatic load of dietary restriction
Pijl, H. (2011) · Physiology & Behavior · doi:10.1016/j.physbeh.2011.05.030 · Cited by 12
Mulvey, L., Wilkie, S. E., Borland, G., Griffiths, K., Sinclair, A., McGuinness, D., Watson, D. G., & Selman, C. (2021) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2021.111376 · Cited by 13
“In ILSXISS strains, it has previously been reported that those strains that showed the greatest lifespan extension under 40% CR also lost the least amount of fat relative to their strain-specific AL controls when measured at 15–17 months and 20–22 months of age (Liao et al., 2011).”
BackgroundInfluential90th Anniversary Commentary: Caloric Restriction Effects on Aging
Couteur, D. G. L., & Simpson, S. J. (2018) · Journal of Nutrition · doi:10.1093/jn/nxy146 · Cited by 11
Alive and well? Exploring disease by studying lifespan
Brett, J. O., & Rando, T. A. (2014) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2014.05.004 · Cited by 12
Visceral adiposity, metabolic health and aging
Maeyens, L. T., Nelson, J. F., & Zhao, S. (2026) · Nature Aging · doi:10.1038/s43587-026-01076-4 · Cited by 15
Self-citationFelthaus, O., Schön, T., Schiltz, D., Aung, T., Kuehlmann, B. A., Jung, F., Anker, A., Klein, S., & Prantl, L. (2018) · Clinical Hemorheology and Microcirculation · doi:10.3233/ch-189107 · Cited by 11
“Interestingly, both caloric restriction and rapamycin have a positive effect on murine lifespan [55, 56].”
Smith, D. L., Mitchell, S. E., Johnson, M. S., Gibbs, V. K., Dickinson, S., Henschel, B., Li, R., Kaiser, K. A., Chusyd, D. E., Brown, A. W., et al. (2024) · GeroScience · doi:10.1007/s11357-024-01166-4 · Cited by 12
Rzheshevsky, A. V. (2014) · Biochemistry (Moscow) · doi:10.1134/s0006297914100071 · Cited by 11
Reversing age-associated arterial dysfunction: insight from preclinical models
Gogulamudi, V. R., Cai, J., & Lesniewski, L. A. (2018) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00086.2018 · Cited by 11
“Although CR is one of the most effective antiaging interventions, CR is not universally effective, with some studies demonstrating no improvement in age-associated loss of body fat, bone mass, and density in nonhuman primates, as well as no effect or even a shortened life span in some inbred mouse strains (81, 82, 112…”
BackgroundAging: a New Perspective on an Old Issue
Mori, M. A. (2020) · Anais da Academia Brasileira de Ciências · doi:10.1590/0001-3765202020200437 · Cited by 10
Unlocking metabolic insights with mouse genetic diversity
Masson, S. W. C., Cutler, H. B., & James, D. E. (2024) · The EMBO Journal · doi:10.1038/s44318-024-00221-2 · Cited by 9
“One classic example where multi-strain studies have exposed the true complexity of a biological process relates to the belief that calorie restriction (CR) has universally bene fi cial effects on extending lifespan (Liao et al, 2011).”
Jurrjens, A. W., Seldin, M. M., Giles, C., Meikle, P. J., Drew, B. G., & Calkin, A. C. (2023) · eLife · doi:10.7554/elife.86139 · Cited by 11
Ishaq, A., Dufour, D., Cameron, K., von Zglinicki, T., & Saretzki, G. C. (2018) · Experimental Gerontology · doi:10.1016/j.exger.2018.10.008 · Cited by 10
“Intriguingly, fat reduction during DR correlated inversely to life extension in male mice (Liao et al., 2011).”
Body macronutrient composition is predicted by lipid and not protein content of the diet
Moatt, J. P., Hambly, C., Heap, E. A., Kramer, A., Moon, F., Speakman, J. R., & Walling, C. A. (2017) · Ecology and Evolution · doi:10.1002/ece3.3529 · Cited by 7
“However, contradictory evidence suggests that fat loss under calorie restriction provided no benefit or was detrimental to lifespan (Chiba et al., 2014; Liao et al., 2011; Park et al., 2017).”
BackgroundReshaping lipid metabolism with long-term alternate day feeding in type 2 diabetes mice
Beli, E., Yan, Y., Moldovan, L., Lydic, T. A., Krishman, P., Tersey, S. A., Duan, Y., Salazar, T. E., Dominguez, J. M., Nguyen, D. V., et al. (2025) · npj Metabolic Health and Disease · doi:10.1038/s44324-024-00039-w · Cited by 6
“Our study also supports those of Harney et al. and Liao et al., as both demonstrate fat maintenance during calorie restriction conditions or IF and despiteno weight loss better survival in mouse models 12,54 .”
Mitchell, S. J., & Mitchell, J. R. (2022) · Nutrition and Healthy Aging · doi:10.3233/nha-220162 · Cited by 9
Fat-containing cells are eliminated duringDictyosteliumdevelopment
Kornke, J. M., & Maniak, M. (2017) · Biology Open · doi:10.1242/bio.025478 · Cited by 5
“Low TAG levels originating from caloric restriction can shorten the lifespan of mice (Liao et al., 2011), while the same condition produced by genetic loss of the DGAT1 enzyme promotes longevity (Streeper et al.”
BackgroundMitchell, S. E., Togo, J., Green, C. L., Derous, D., Hambly, C., & Speakman, J. R. (2023) · The Journals of Gerontology Series A · doi:10.1093/gerona/glad152 · Cited by 8
“Although some have pinpointed the reduction in fat mass as a key factor to predict life extension under CR (29,30), others have conversely suggested that maintenance of fat mass is vital for survival (31).”
BackgroundPhillips, D., Mathers, H., Mitchell, S. E., & Speakman, J. R. (2022) · The Journals of Gerontology Series A · doi:10.1093/gerona/glac110 · Cited by 5
“(38) found that CR was more likely to extend life span in mice strains that protected their fat stores and suggested that some of this benefit may have arisen from the redistribution of subcutaneous fat stores over visceral ones, as has been found in C57BL/6 females (39).”
ResultGijsen, H. S. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-55035-6_16 · Cited by 6
Time-restricted feeding extends healthspan in both sexes and lifespan in male C57BL/6 J mice
Iiams, S. E., Skinner, N. J., Wight‐Carter, M., Acosta-Rodríguez, V. A., Green, C. B., & Takahashi, J. S. (2026) · Nature Aging · doi:10.1038/s43587-026-01129-8 · Cited by 6
Mechanisms underlying retardation of aging by dietary energy restriction
Shimokawa, I. (2023) · Pathology International · doi:10.1111/pin.13387 · Cited by 3
Metadata
- Authors
- Liao, C., Rikke, B. A., Johnson, T. E., Gelfond, J. A. L., Diaz, V., & Nelson, J. F.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- University of Colorado Boulder (US)
- Corresponding author
- Nelson, James F.
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2011-04-25
- Volume
- 10
- Issue
- 4
- Pages
- 629-639
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- PMC
- PMC3685291
- OpenAlex
- W1542109194
- Cited by
- 120
- References
- 71
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 6 · 2023: 6 · 2022: 6 · 2021: 8 · 2020: 11 · 2019: 7 · 2018: 10 · 2017: 10 · 2016: 6 · 2015: 14 · 2014: 14 · 2013: 5 · 2012: 7
- FWCI
- 3.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Aging Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Ellison Medical Foundation
- Glenn Foundation for Medical Research
- National Institute on Aging (1 RO1 AG024354, R01AG024354)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Physiology (medical) › Dietary Effects on Health
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- dietary restriction, lifespan extension, adiposity, fat mass, recombinant inbred mouse strains, quantitative trait loci, longevity, fuel economy, age-related diseases, sex differences
- MeSH terms
- Animals, Dietary Fats, Female, Longevity, Male, Mice, Inbred Strains, Genetic Variation, Caloric Restriction, Quantitative Trait Loci, Adiposity, Mice
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