Low insulin‐like growth factor‐1 level predicts survival in humans with exceptional longevity

Milman, Sofiya; Atzmon, Gil; Huffman, Derek M.; Wan, Junxiang; Crandall, Jill P.; Cohen, Pinchas; Barzilai, Nir

doi:10.1111/acel.12213

Cited by 176 publications

(144 citation statements)

References 10 publications

Supporting

Mentioning

134

Contrasting

Unclassified

Order By: Relevance

“…In humans, low levels of IGF-1 and mutations in IGFR have been associated with enhanced longevity in females (Milman et al 2014;Suh et al 2008;van Heemst et al 2005). Moreover, patients with Laron's syndrome (an autosomal recessive disorder characterized by an insensitivity to GH caused by a mutation in the GH receptor) have been shown to be protected from cancer and diabetes, although these individuals do not live significantly longer than their healthy counterparts (as reviewed by Sonntag et al (2012)).…”

Section: Discussionmentioning

confidence: 99%

IGF-1 has sexually dimorphic, pleiotropic, and time-dependent effects on healthspan, pathology, and lifespan

et al. 2017

View full text Add to dashboard Cite

Reduced circulating levels of IGF-1 have been proposed as a conserved anti-aging mechanism that contributes to increased lifespan in diverse experimental models. However, IGF-1 has also been shown to be essential for normal development and the maintenance of tissue function late into the lifespan. These disparate findings suggest that IGF-1 may be a pleiotropic modulator of health and aging, as reductions in IGF-1 may be beneficial for one aspect of aging, but detrimental for another. We postulated that the effects of IGF-1 on tissue health and function in advanced age are dependent on the tissue, the sex of the animal, and the age at which IGF-1 is manipulated. In this study, we examined how alterations in IGF-1 levels at multiple stages of development and aging influence overall lifespan, healthspan, and pathology. Specifically, we investigated the effects of perinatal, post-pubertal, and late-adult onset IGF-1 deficiency using genetic and viral approaches in both male and female igf f/f C57Bl/6 mice. Our results support the concept that IGF-1 levels early during lifespan establish the conditions necessary for subsequent healthspan and pathological changes that contribute to aging. Nevertheless, these changes are specific for each sex and tissue. Importantly, late-life IGF-1 deficiency (a time point relevant for human studies) reduces cancer risk but does not increase lifespan. Overall, our results indicate that the levels of IGF-1 during development influence late-life pathology, suggesting that IGF-1 is a developmental driver of healthspan, pathology, and lifespan.

show abstract

Section: Discussionmentioning

confidence: 99%

IGF-1 has sexually dimorphic, pleiotropic, and time-dependent effects on healthspan, pathology, and lifespan

et al. 2017

View full text Add to dashboard Cite

show abstract

“…The IIS pathway is the most evolutionarily conserved pathway of aging, shown to modulate lifespan in model organisms across a great evolutionary distance from Caenorhabditis elegans to mice (Kimura et al ., 1997; Tatar et al ., 2001; Fontana et al ., 2010; Kenyon, 2010b; Mercken et al ., 2013). Accordingly, genetic polymorphisms/mutations that cause loss of function of GH, IGF‐1 receptor, insulin receptor or its downstream factors, have been implicated in human longevity as in model organisms (Fontana et al ., 2010; Kenyon, 2010b; Tazearslan et al ., 2011; Barzilai et al ., 2012; Milman et al ., 2014). Dietary restriction is a well‐known environmental signal shown to expand lifespan in eukaryote species, from yeast to primates (Colman et al ., 2009; Fontana et al ., 2010; Mattison et al ., 2012).…”

Section: Introductionmentioning

confidence: 99%

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

2015

View full text Add to dashboard Cite

SummaryAging constitutes the key risk factor for age‐related diseases such as cancer and cardiovascular and neurodegenerative disorders. Human longevity and healthy aging are complex phenotypes influenced by both environmental and genetic factors. The fact that genetic contribution to lifespan strongly increases with greater age provides basis for research on which “protective genes” are carried by long‐lived individuals. Studies have consistently revealed FOXO (Forkhead box O) transcription factors as important determinants in aging and longevity. FOXO proteins represent a subfamily of transcription factors conserved from Caenorhabditis elegans to mammals that act as key regulators of longevity downstream of insulin and insulin‐like growth factor signaling. Invertebrate genomes have one FOXO gene, while mammals have four FOXO genes: FOXO1, FOXO3, FOXO4, and FOXO6. In mammals, this subfamily is involved in a wide range of crucial cellular processes regulating stress resistance, metabolism, cell cycle arrest, and apoptosis. Their role in longevity determination is complex and remains to be fully elucidated. Throughout this review, the mechanisms by which FOXO factors contribute to longevity will be discussed in diverse animal models, from Hydra to mammals. Moreover, compelling evidence of FOXOs as contributors for extreme longevity and health span in humans will be addressed.

show abstract

“…In PAPP-A KO mice, circulating levels of IGF-1 are not different when compared to normal littermates (Conover and Bale 2007). However, bioactive IGF-1 is decreased, highlighting a role of IGF-1 levels in relation to lifespan, as already established in various types of dwarf mice with low growth hormone signaling (Berryman et al 2008;Brown-Borg et al 1996;Bartke et al 2005) and suggested by recent findings in humans (Milman et al 2014).…”

Section: Introductionmentioning

confidence: 73%

“…Longevity and aging are strongly associated with insulin-like growth factor-1 (IGF-1) and insulin signaling, which share common intracellular pathways (Milman et al 2014;Berryman et al 2008;BrownBorg et al 1996;Bartke 2003;2005). Effects of IGF-1 resemble the effects of insulin, and IGF-1 generally promotes insulin signaling in the cell (Blundell and Humbell 1980).…”

Section: Introductionmentioning

confidence: 99%

Female PAPP-A knockout mice are resistant to metabolic dysfunction induced by high-fat/high-sucrose feeding at middle age

Hill

Arum

Boparai

et al. 2015

AGE

View full text Add to dashboard Cite

Longevity and aging are influenced by common intracellular signals of the insulin/insulin-like growth factor (IGF)-1 pathway. Abnormally high levels of bioactive IGF-1 increase the development of various cancers and may contribute to metabolic diseases such as insulin resistance. Enhanced availability of IGF-1 is promoted by cleavage of IGF binding proteins (IGFBPs) by proteases, including the pregnancyassociated plasma protein-A (PAPPA). In vitro, PAPP-A is regulated by pro-inflammatory cytokines (PICs) such as interleukin (IL)-6 and tumor necrosis factor (TNF). Mice born with deficiency of the Papp-a gene (PAPP-A knockout (KO) mice) live ∼30-40 % longer than their normal littermates and have decreased bioactive IGF-1 on standard diets. Our objective was to elucidate how the effects of high-fat, high-sucrose diet (HFHS) promote obesity, induce metabolic dysfunction, and alter systemic cytokine expression in PAPP-A KO and normal mice. PAPP-A KO mice fed HFHS diet for 10 weeks were more glucose tolerant and had enhanced insulin sensitivity compared to normal mice fed HFHS diet. PAPP-A KO mice fed HFHS diet had lower levels of pro-inflammatory cytokines (IL-2, IL-6, and TNF-α) compared to normal mice fed the same diet. However, anti-inflammatory cytokine levels (IL-4 and adiponectin) were higher in PAPP-A KO mice fed AGE (2015) 37: 51

show abstract

Low insulin‐like growth factor‐1 level predicts survival in humans with exceptional longevity

Cited by 176 publications

References 10 publications

IGF-1 has sexually dimorphic, pleiotropic, and time-dependent effects on healthspan, pathology, and lifespan

IGF-1 has sexually dimorphic, pleiotropic, and time-dependent effects on healthspan, pathology, and lifespan

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

Female PAPP-A knockout mice are resistant to metabolic dysfunction induced by high-fat/high-sucrose feeding at middle age

Contact Info

Product

Resources

About