Late-life targeting of the IGF-1 receptor improves healthspan and lifespan in female mice

Mao, Kai; Quipildor, Gabriela Farias; Tabrizian, Tahmineh; Novaj, Ardijana; Guan, Fangxia; Walters, Ryan O.; Delahaye, Fabien; Hubbard, Gene B.; Ikeno, Yuji; Ejima, Keisuke; Li, Peng; Allison, David B.; Salimi-Moosavi, Hossein; Beltran, Pedro J.; Cohen, Pinchas; Barzilai, Nir; Huffman, Derek M.

doi:10.1038/s41467-018-04805-5

Cited by 126 publications

(99 citation statements)

References 52 publications

(81 reference statements)

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“…Further research will be required to distinguish between these possibilities and to determine the role of IGF‐1 in the metabolic effects we observed. Reduced signaling through the growth hormone/IGF‐1 axis due to genetic mutations or caloric restriction is associated with increased healthspan and lifespan in model organisms (Mao et al, ; Milman, Huffman, & Barzilai, ). These results support the idea that the early‐onset obesity observed in Rictor Nkx2.1−/− mice and the higher circulating level of IGF‐1 could have a combined long‐term negative impact on health and lifespan.…”

Section: Discussionmentioning

confidence: 99%

Hypothalamic mTORC2 is essential for metabolic health and longevity

et al. 2019

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The mechanistic target of rapamycin (mTOR) is an evolutionarily conserved protein kinase that regulates growth and metabolism. mTOR is found in two protein complexes, mTORC1 and mTORC2, that have distinct components and substrates and are both inhibited by rapamycin, a macrolide drug that robustly extends lifespan in multiple species including worms and mice. Although the beneficial effect of rapamycin on longevity is generally attributed to reduced mTORC1 signaling, disruption of mTORC2 signaling can also influence the longevity of worms, either positively or negatively depending on the temperature and food source. Here, we show that loss of hypothalamic mTORC2 signaling in mice decreases activity level, increases the set point for adiposity, and renders the animals susceptible to diet‐induced obesity. Hypothalamic mTORC2 signaling normally increases with age, and mice lacking this pathway display higher fat mass and impaired glucose homeostasis throughout life, become more frail with age, and have decreased overall survival. We conclude that hypothalamic mTORC2 is essential for the normal metabolic health, fitness, and lifespan of mice. Our results have implications for the use of mTORC2‐inhibiting pharmaceuticals in the treatment of brain cancer and diseases of aging.

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Section: Discussionmentioning

confidence: 99%

Hypothalamic mTORC2 is essential for metabolic health and longevity

et al. 2019

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“…Total protein was mechanically homogenized and extracted with denaturing lysis buffer (150mM NaCl, 50mM Tris-HCl (pH 7.4), 0.25% DOC, 5mM EDTA, 1% Triton X-100, 1mM orthovanadate, 100mM NaF, 5mM Na Pyrophosphate, 1× PIC, and 100uM PMSF) and protein content was determined using the BCA protein assay (Sigma, St. Louis, MO) with BSA as a standard, as described (Mao et al, 2018). Proteins were separated by SDS-PAGE using Bis-Tris stain-free gels (BioRad, Hercules, CA), and total protein was imaged and quantified to confirm equal loading.…”

Section: Star⋆methodsmentioning

confidence: 99%

Sarcosine Is Uniquely Modulated by Aging and Dietary Restriction in Rodents and Humans

et al. 2018

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SUMMARY A hallmark of aging is a decline in metabolic homeostasis, which is attenuated by dietary restriction (DR). However, the interaction of aging and DR with the metabolome is not well understood. We report that DR is a stronger modulator of the rat metabolome than age in plasma and tissues. A comparative metabolomic screen in rodents and humans identified circulating sarcosine as being similarly reduced with aging and increased by DR, while sarcosine is also elevated in long-lived Ames dwarf mice. Pathway analysis in aged sarcosine-replete rats identify this biogenic amine as an integral node in the metabolome network. Finally, we show that sarcosine can activate autophagy in cultured cells and enhances autophagic flux in vivo, suggesting a potential role in autophagy induction by DR. Thus, these data identify circulating sarcosine as a biomarker of aging and DR in mammalians and may contribute to age-related alterations in the metabolome and in proteostasis.

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“…In additional to this smaller lifeextension, reduced IGF1 signalling also appears to have a greater effect on female lifespan than that of males, an effect that has been observed across several different manipulations of the IGF1 pathway, including heterozygous deletion of the IGFR receptor (IGF1R+/-) [29][30][31], conditional knockout of hepatic IGF1 production [32], mice with a hypomorphic IGF1 gene that have low expression levels of IGF1 [33], and pregnancy-associated plasma protein A knockout mice, which show a decrease in IGF1 availability [34]. In addition to observed lifespan effects, improvements in late-life function are observed in female mice treated with an antibody that antagonizes IGF1R [35], but not males, and female IGF1R+/mice show increased paraquat resistance in adulthood but males do not [29,30]. A sex-specificity in the GH-IGF1 pathway for lifespan responses may also be manifest by manipulations further downstream, since disrupted expression of insulin-receptor substrate 2, which transduces information from IGF1R, extends lifespan in females but not males [36] (although the authors acknowledge this may be a consequence of sample size).…”

Section: How Do We Know a Manipulation Has A Sex-specific Effect?mentioning

confidence: 99%

Why do sexes differ in lifespan extension? Sex-specific pathways of aging and underlying mechanisms for dimorphic responses

Garratt

2020

NHA

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Males and females typically have different lifespans and frequently differ in their responses to anti-aging interventions. These sex-specific responses are documented both in mice and Drosophila species, in addition to other organisms where interventions have been tested. While the prevalence of sex-specific responses to anti-aging interventions is now recognised, the underlying causes remain poorly understood. This review first summarises the main pathways and interventions that lead to sex-specific lifespan responses, including the growth-hormone/insulin-like growth factor 1 (GH-IGF1) axis, mechanistic target of rapamycin (mTOR) signalling, and nutritional and pharmacological interventions. After summarising current evidence, several different potential causes for sex-specific responses are discussed. These include sex-differences in xenobiotic metabolism, disease susceptibility, sex-specific hormone production and chromosomes, and the relative importance of different signalling pathways in the control of male and female life-history. Understanding why sex-differences in lifespan-extension occur should provide a greater understanding of the mechanisms that regulate the aging process in each sex, and will be crucial for understanding the full implications of these treatments if they are translated to humans.

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Late-life targeting of the IGF-1 receptor improves healthspan and lifespan in female mice

Cited by 126 publications

References 52 publications

Hypothalamic mTORC2 is essential for metabolic health and longevity

Hypothalamic mTORC2 is essential for metabolic health and longevity

Sarcosine Is Uniquely Modulated by Aging and Dietary Restriction in Rodents and Humans

Why do sexes differ in lifespan extension? Sex-specific pathways of aging and underlying mechanisms for dimorphic responses

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