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 103 publications

(78 citation statements)

References 122 publications

(184 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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

View full text Add to dashboard Buy / Rent full text

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.

show abstract

Section: Resultsmentioning

confidence: 99%

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

et al. 2018

View full text Add to dashboard Buy / Rent full text

show abstract

“…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

View full text Add to dashboard Buy / Rent full text

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.

show abstract

“…Intriguingly, FTT associated with pediatric heart disease often features lower circulating insulin-like growth factor 1 (IGF1) and IGF binding protein 3 (IGFBP3) levels (Barton et al, 1996;Dinleyici et al, 2007;Surmeli-Onay et al, 2011;Peng et al, 2013). GH-IGF1 signaling is a dominant mechanism regulating postnatal mammalian growth (Pilecka et al, 2007;Baik et al, 2011;Savage et al, 2011;Rotwein, 2012;Milman et al, 2016). GH secreted from the pituitary signals to the liver to stimulate the production of IGF1, IGFBP3, and IGFBP acid-labile subunit (IGFALS) via the JAK2-STAT5 pathway.…”

Section: Introductionmentioning

confidence: 99%

GDF 15 is a heart‐derived hormone that regulates body growth

et al. 2017

View full text Add to dashboard Buy / Rent full text

The endocrine system is crucial for maintaining whole‐body homeostasis. Little is known regarding endocrine hormones secreted by the heart other than atrial/brain natriuretic peptides discovered over 30 years ago. Here, we identify growth differentiation factor 15 (GDF15) as a heart‐derived hormone that regulates body growth. We show that pediatric heart disease induces GDF15 synthesis and secretion by cardiomyocytes. Circulating GDF15 in turn acts on the liver to inhibit growth hormone (GH) signaling and body growth. We demonstrate that blocking cardiomyocyte production of GDF15 normalizes circulating GDF15 level and restores liver GH signaling, establishing GDF15 as a bona fide heart‐derived hormone that regulates pediatric body growth. Importantly, plasma GDF15 is further increased in children with concomitant heart disease and failure to thrive (FTT). Together these studies reveal a new endocrine mechanism by which the heart coordinates cardiac function and body growth. Our results also provide a potential mechanism for the well‐established clinical observation that children with heart diseases often develop FTT.

show abstract

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

Cited by 103 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?

GDF 15 is a heart‐derived hormone that regulates body growth

Contact Info

Product

Resources

About