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, Leland; Barzilai, Nir; Verghese, Joe; Weiss, Erica; Holtzer, Roee; Cohen, Pinchas; Milman, Sofiya

doi:10.18632/aging.101063

Cited by 26 publications

(33 citation statements)

References 66 publications

(72 reference statements)

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“…Our findings are more similar to that reported by Doi and colleagues (Doi et al 2015(Doi et al 2016 where lower levels of IGF-1 were associated with both slow gait speed (Doi et al 2015) and incident disability (Doi et al 2016). However, other studies have found the opposite (Meng et al 2015) or no association (Perice et al 2016). Therefore, whether a relationship exists between IGF-1 concentrations and gait speed in males or females remains an enigma.…”

Section: Discussionsupporting

confidence: 89%

“…These include structural and functional brain changes, endocrine dysregulation including changes in growth hormone, thyroid hormone, adrenocorticoids, estradiol and testosterone and metabolic processes including dysregulation of carbohydrate and energy metabolism (leptin, adiponectin), insulin signalling, vitamin D metabolism and changes in body composition. Chronic inflammatory markers such as IL-6, C-reactive protein, interleukin-1-receptor agonist, interleukin-18, and soluble TNF-α receptor 1 and metabolomics have also been proposed (Rodriguez-Manas et al 2019;Pujos-Guillot et al 2019). More general biomarkers were proposed by Kane and Sinclair (Kane and Sinclair 2019) including low albumin, markers of anaemia (haemoglobin, iron, ferritin), total cholesterol, LDL and low creatinine, and these investigators also stressed the importance of controlling for sex differences in identifying biomarkers.…”

mentioning

confidence: 99%

Sex-specific muscle and metabolic biomarkers associated with gait speed and cognitive transitions in older adults: a 9-year follow-up

et al. 2020

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Physical frailty and cognitive frailty share biological mechanisms, but sex-specific biomarkers associated with transitions in gait speed and cognition during ageing are poorly understood.Gait speed, cognition (3MSE), body composition (DXA) and serological biomarkers were assessed annually over 9 years in 216 males (72.7 + 8.07 years) and 384 females (71.1 + 8.44 years). In females, maintaining normal gait speed was associated with lower percent body fat (IRR 0.793, p = 0.001, 95%CI 0.691-0.910) and lower lactate dehydrogenase (LDH) (IRR 0.623, p = 0.00, 95%CI 0.514-0.752), and in males, the association was with higher cholesterol (IRR 1.394, p = 0.001, 95%CI 1.154-1.684). Abnormal to normal gait speed transitions were associated with higher insulin in females (IRR 1.325, p = 0.022, 95%CI 1.041-1.685) and lower creatinine in males (IRR 0.520, p = 0.01, 95%CI 0.310-0.870). Normal to slow gait speed transitions in males were associated with IGF-1 (IRR 1.74, p = 0.022, 95%CI 1.08-2.79) and leptin in females (IRR 1.39, p = 0.043, 95%CI 1.01-1.91.) Maintaining normal cognition was associated with lower LDH in females (IRR 0.276, p = 0.013, 95%CI 0.099-0.765) and higher appendicular skeletal muscle mass in males (IRR 1.52, p = 0.02, 95%CI 1.076-2.135). Improved cognition was associated with higher leptin (IRR 7.5, p = 0.03, 95%CI 1.282-44.34) and lower triglyceride (IRR 0.299, p = 0.017, 95%CI 0.110-0.809) in males. Education was protective against cognitive decline in females (IRR 0.84, p = 0.037, 0.732-0.982). Sexspecific biomarkers of muscle (LDH, Creatinine, IGF-1, APSM) and metabolism (%fat, insulin,cholesterol, leptin, tryglycerides) were associated with gait speed and cognitive transitions. These data suggest that modifiable biomarkers of muscle and metabolism could be targeted for interventions.

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“…In this study of very old Ashkenazi Jews over 95 years of age, women (n=163) within the higher tertile ranges of IGF-1 had worse cognitive results on MMSE testing (Perice et al 2016). In this age group, they also found no association between IGF-1 concentrations and cognitive impairment in men, although the study only included a modest number of men (n=40) compared with 163 women (Perice et al 2016). This is the first study to show no association between IGF-1 and cognition in older adults.…”

Section: Human Observational Studies In Healthy Adultsmentioning

confidence: 65%

Insulin-like Growth Factor 1 (IGF-1) as a marker of cognitive decline in normal ageing: A review

Frater

Lie

Bartlett

et al. 2018

Ageing Research Reviews

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Insulin-like Growth Factor 1 (IGF-1) and its signaling pathway play a primary role in normal growth and ageing, however serum IGF-1 is known to reduce with advancing age. Recent findings suggest IGF-1 is essential for neurogenesis in the adult brain, and this reduction of IGF-1 with ageing may contribute to age-related cognitive decline. Experimental studies have shown manipulation of the GH/GF-1 axis can slow rates of cognitive decline in animals, making IGF-1 a potential biomarker of cognition, and/or its signaling pathway a possible therapeutic target to prevent or slow age-related cognitive decline. A systematic literature review and qualitative narrative summary of current evidence for IGF-1 as a biomarker of cognitive decline in the ageing brain was undertaken. Results indicate IGF-1 concentrations do not confer additional diagnostic information for those with cognitive decline, and routine clinical measurement of IGF-1 is not currently justified. In cases of established cognitive impairment, it remains unclear whether increasing circulating or brain IGF-1 may reverse or slow down the rate of further decline. Advances in neuroimaging, genetics, neuroscience and the availability of large well characterized biobanks will facilitate research exploring the role of IGF-1 in both normal ageing and age-related cognitive decline.

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“…Biochemical measurements were performed as previously described [41]. Total IGF-1 levels were measured by liquid chromatography/mass spectrometry at Quest Diagnostics Nichols Institute laboratories (Quest, San Juan Capistrano, CA, USA) in serum collected at baseline and subsequently stored at −80 • C. For IGF-1, the limit of quantification (LOQ) was 15.6 ng/mL and the coefficient of variance (CV) was 3.3%, 3.1%, 2.8%, and 5% for the low (mean 57.2 ng/mL), medium (mean 248 ng/mL), high (mean 447.1 ng/mL) Bio-Rad quality controls and pooled human serum in-house control (mean 104 ng/mL), respectively.…”

Section: Biochemical Measurementsmentioning

confidence: 99%

Insulin-like Growth Factor-1 and IGF Binding Proteins Predict All-Cause Mortality and Morbidity in Older Adults

Zhang

Aleksic

Gao

et al. 2020

Cells

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While the growth hormone/insulin-like growth factor-1 (GH/IGF-1) pathway plays essential roles in growth and development, diminished signaling via this pathway in model organisms extends lifespan and health-span. In humans, circulating IGF-1 and IGF-binding proteins 3 and 1 (IGFBP-3 and 1), surrogate measures of GH/IGF-1 system activity, have not been consistently associated with morbidity and mortality. In a prospective cohort of independently-living older adults (n = 840, mean age 76.1 ± 6.8 years, 54.5% female, median follow-up 6.9 years), we evaluated the age- and sex-adjusted hazards for all-cause mortality and incident age-related diseases, including cardiovascular disease, diabetes, cancer, and multiple-domain cognitive impairment (MDCI), as predicted by baseline total serum IGF-1, IGF-1/IGFBP-3 molar ratio, IGFBP-3, and IGFBP-1 levels. All-cause mortality was positively associated with IGF-1/IGFBP-3 molar ratio (HR 1.28, 95% CI 1.05–1.57) and negatively with IGFBP-3 (HR 0.82, 95% CI 0.680–0.998). High serum IGF-1 predicted greater risk for MDCI (HR 1.56, 95% CI 1.08–2.26) and composite incident morbidity (HR 1.242, 95% CI 1.004–1.538), whereas high IGFBP-1 predicted lower risk for diabetes (HR 0.50, 95% CI 0.29–0.88). In conclusion, higher IGF-1 levels and bioavailability predicted mortality and morbidity risk, supporting the hypothesis that diminished GH/IGF-1 signaling may contribute to human longevity and health-span.

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“…These studies also indicate that the difference in 'relative risk' of living to 90 or 95 years is very marginal, which suggests limited heritability of longevity at these ages. Moreover, multiple extreme long-lived individuals are classified as ³ 95 years of age, regardless of gender (Ayers et al, 2017;Deluty et al, 2015;Gubbi et al, 2017;Perice et al, 2016). As females generally live to older ages, we calculated and applied a sex-specific age threshold for long-lived status.…”

Section: Exome-and Genome-wide Association Analysis Of Long-lived Casmentioning

confidence: 99%

Exome-wide association studies in general and long-lived populations identify genetic variants related to human age

Sin-Chan

Gosalia

Palmer

et al. 2020

Preprint

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Aging is characterized by degeneration in cellular and organismal functions leading to increased disease susceptibility and death. Although our understanding of aging biology in model systems has increased dramatically, large-scale sequencing studies to understand human aging are now just beginning. We applied exome sequencing and association analyses (ExWAS) to identify age-related variants on 58,470 participants of the DiscovEHR cohort. Linear Mixed Model regression analyses of age at last encounter revealed variants in genes known to be linked with clonal hematopoiesis of indeterminate potential, which are associated with myelodysplastic syndromes, as top signals in our analysis, suggestive of age-related somatic mutation accumulation in hematopoietic cells despite patients lacking clinical diagnoses. In addition to APOE, we identified rare DISP2 rs183775254 (p = 7.40x10-10) and ZYG11A rs74227999 (p = 2.50x10-08) variants that were negatively associated with age in either both sexes combined and females, respectively, which were replicated with directional consistency in two independent cohorts. Epigenetic mapping showed these variants are located within cell-type-specific enhancers, suggestive of important transcriptional regulatory functions. To discover variants associated with extreme age, we performed exome-sequencing on persons of Ashkenazi Jewish descent ascertained for extensive lifespans. Case-Control analyses in 525 Ashkenazi Jews cases (Males greater than 92 years, Females greater than 95years) were compared to 482 controls. Our results showed variants in APOE (rs429358, rs6857), and TMTC2 (rs7976168) passed Bonferroni-adjusted p-value, as well as several nominally-associated population-specific variants. Collectively, our Age-ExWAS, the largest performed to date, confirmed and identified previously unreported candidate variants associated with human age.

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

Cited by 26 publications

References 66 publications

Sex-specific muscle and metabolic biomarkers associated with gait speed and cognitive transitions in older adults: a 9-year follow-up

Insulin-like Growth Factor 1 (IGF-1) as a marker of cognitive decline in normal ageing: A review

Insulin-like Growth Factor-1 and IGF Binding Proteins Predict All-Cause Mortality and Morbidity in Older Adults

Exome-wide association studies in general and long-lived populations identify genetic variants related to human age

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