The Somatotropic Axis in Human Aging: Framework for the Current State of Knowledge and Future Research

Milman, Sofiya; Huffman, Derek M.; Barzilai, Nir

doi:10.1016/j.cmet.2016.05.014

Cited by 113 publications

(80 citation statements)

References 122 publications

(184 reference statements)

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“…The insulin growth factor 1 (Igf‐1) and its receptor (Igf‐1r; Kenyon, 2005; Longo & Finch, 2003; Milman, Huffman, & Barzilai, 2016), as well as the stemness potential of stem cells (Garcia‐Prat et al, 2016; Garcia‐Prat, Sousa‐Victor, & Munoz‐Canoves, 2017), represent already established age‐associated pathways. To determine whether they were mechanistically involved—at least in part—in the AT‐1 sTg phenotype, we analyzed whole tissue activation of Igf‐1r signaling (Supporting Information Figure S4a,b); we also treated cultured MEF with Igf‐1 (Supporting Information Figure S4c,d).…”

Section: Resultsmentioning

confidence: 99%

Increased transport of acetyl‐CoA into the endoplasmic reticulum causes a progeria‐like phenotype

et al. 2018

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The membrane transporter AT‐1/SLC33A1 translocates cytosolic acetyl‐CoA into the lumen of the endoplasmic reticulum (ER), participating in quality control mechanisms within the secretory pathway. Mutations and duplication events in AT‐1/SLC33A1 are highly pleiotropic and have been linked to diseases such as spastic paraplegia, developmental delay, autism spectrum disorder, intellectual disability, propensity to seizures, and dysmorphism. Despite these known associations, the biology of this key transporter is only beginning to be uncovered. Here, we show that systemic overexpression of AT‐1 in the mouse leads to a segmental form of progeria with dysmorphism and metabolic alterations. The phenotype includes delayed growth, short lifespan, alopecia, skin lesions, rectal prolapse, osteoporosis, cardiomegaly, muscle atrophy, reduced fertility, and anemia. In terms of homeostasis, the AT‐1 overexpressing mouse displays hypocholesterolemia, altered glycemia, and increased indices of systemic inflammation. Mechanistically, the phenotype is caused by a block in Atg9a‐Fam134b‐LC3β and Atg9a‐Sec62‐LC3β interactions, and defective reticulophagy, the autophagic recycling of the ER. Inhibition of ATase1/ATase2 acetyltransferase enzymes downstream of AT‐1 restores reticulophagy and rescues the phenotype of the animals. These data suggest that inappropriately elevated acetyl‐CoA flux into the ER directly induces defects in autophagy and recycling of subcellular structures and that this diversion of acetyl‐CoA from cytosol to ER is causal in the progeria phenotype. Collectively, these data establish the cytosol‐to‐ER flux of acetyl‐CoA as a novel event that dictates the pace of aging phenotypes and identify intracellular acetyl‐CoA‐dependent homeostatic mechanisms linked to metabolism and inflammation.

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Section: Resultsmentioning

confidence: 99%

Increased transport of acetyl‐CoA into the endoplasmic reticulum causes a progeria‐like phenotype

et al. 2018

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“…In mice and men, the somatotropic axis occupy a central position in the study of ageing, health-span, and longevity (195,196,197,198,199,200,201). GHD mouse models have consistently shown an extended lifespan, while the results are inconsistent in GHD humans (200,202,203).…”

Section: Ageing and Longevitymentioning

confidence: 99%

“…Low serum IGF-1 levels is undoubtedly an important factor for increased lifespan of the GHRKO mice as IGF-1 deficiency alone is known to extend maximum but not mean lifespan (196,212,213). Additional factors that lead to the GHRKO mice being the longest-lived mouse in the world include the following -(i) increased stress resistance resulting from superior redox homeostasis due to upregulated expression and activity of glutaredoxin and thioredoxin detoxification systems (214,215,216,217) rather than changes in free-radical scavenging(218), (ii) reduced activity of TORC1 kinase complex (219, 220, 221), (iii) resistance to neoplastic incidence and growth(24, 97), (iv) suppressed hypothalamic inflammation(222) -an end-goal of anti-ageing drugs(223), (v) an anti-inflammatory adipokine profile, inverted liver-WAT lipid distribution and reduced senescent cell burden in WAT(62, 68, 70, 72), (vi) increased markers of mitochondrial biogenesis including higher levels of AMPK, SIRT1, and SIRT3 in heart and increased eNOS and PGC1α levels in skeletal muscle and kidney (224), (vii) detrimental effects of GH/IGF axis on very small embryonic-like stem cell pools in adult tissues (225,226) where age-related changes in DNA methylation patterns lead to increased sensitivity to circulating GH, IGF-1 and insulin with age with concomitant depletion of stem-cell pool and impaired tissue regeneration(225), (viii) resistance to diabetogenic effects of a HF diet (14), and (ix) improved insulin sensitivity(15).…”

Section: Factors For Extended Lifespan Of Ghrko Micementioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Lessons from growth hormone receptor gene-disrupted mice: are there benefits of endocrine defects?

Basu

Qian

Kopchick

2018

European Journal of Endocrinology

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Growth hormone (GH) is produced primarily by anterior pituitary somatotroph cells. Numerous acute human (h) GH treatment and long-term follow-up studies and extensive use of animal models of GH action have shaped the body of GH research over the past 40-50 years. Work on the GH receptor (R) knock-out (GHRKO) mice and results of studies on GH resistant Laron Syndrome (LS) patients have helped define many physiological actions of GH including those dealing with metabolism, obesity, cancer, diabetes, cognition, and aging/longevity. In this review, we have discussed several issues dealing with these biological effects of GH and attempt to answer the question of whether decreased GH action may be beneficial.

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“…Despite evidence from humans and experimental models that reduced circulating IGF-I may promote longevity and healthy lifespan [5, 7–13], the role of peripheral IGF-I in cognition and muscle function remains unresolved [14–16]. Several cross-sectional and prospective studies linked lower IGF-I to poorer cognitive function, as well as higher risk for mild cognitive impairment and Alzheimer's disease [17–19].…”

Section: Introductionmentioning

confidence: 99%

Lower circulating insulin-like growth factor-I is associated with better cognition in females with exceptional longevity without compromise to muscle mass and function

Perice

Barzilai

Weiss

et al. 2016

Aging

Self Cite

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Mutations that reduce somatotropic signaling result in improved lifespan and health-span in model organisms and humans. However, whether reduced circulating insulin-like growth factor-I (IGF-I) level is detrimental to cognitive and muscle function in older adults remains understudied. A cross-sectional analysis was performed in Ashkenazi Jews with exceptional longevity (age ≥95 years). Cognition was assessed using the Mini-Mental State Examination and muscle function with the chair rise test, grip-strength, and gait speed. Muscle mass was estimated using the skeletal muscle index. Serum IGF-I was measured with liquid chromatography mass spectrometry. In gender stratified age-adjusted logistic regression analysis, females with IGF-I levels in the first tertile had lower odds of being cognitively impaired compared to females with IGF-I levels within the upper two tertiles, OR (95% CI) 0.39 (0.19-0.82). The result remained significant after adjustment for multiple parameters. No significant association was identified in males between IGF-I and cognition. No relationship was found between IGF-I tertiles and muscle function and muscle mass in females or males. Lower circulating IGF-I is associated with better cognitive function in females with exceptional longevity, with no detriment to skeletal muscle mass and function.

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The Somatotropic Axis in Human Aging: Framework for the Current State of Knowledge and Future Research

Cited by 113 publications

References 122 publications

Increased transport of acetyl‐CoA into the endoplasmic reticulum causes a progeria‐like phenotype

Increased transport of acetyl‐CoA into the endoplasmic reticulum causes a progeria‐like phenotype

MECHANISMS IN ENDOCRINOLOGY: Lessons from growth hormone receptor gene-disrupted mice: are there benefits of endocrine defects?

Lower circulating insulin-like growth factor-I is associated with better cognition in females with exceptional longevity without compromise to muscle mass and function

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