Age-related decline in circulating IGF-1 associates with impaired neurovascular coupling responses in older adults

Abstract

Impairment of moment-to-moment adjustment of cerebral blood flow (CBF) to the increased oxygen and energy requirements of active brain regions via neurovascular coupling (NVC) contributes to the genesis of age-related cognitive impairment. Aging is associated with marked deficiency in the vasoprotective hormone insulin-like growth factor-1 (IGF-1). Preclinical studies on animal models of aging suggest that circulating IGF-1 deficiency is causally linked to impairment of NVC responses. The present study was designed to test the hypotheses that decreases in circulating IGF-1 levels in older adults also predict the magnitude of age-related decline of NVC responses. In a single-center cross-sectional study, we enrolled healthy young (n = 31, 11 female, 20 male, mean age: 28.4 + / − 4.2 years) and aged volunteers (n = 32, 18 female, 14 male, mean age: 67.9 + / − 4.1 years). Serum IGF-1 level, basal CBF (phase contrast magnetic resonance imaging (MRI)), and NVC responses during the trail making task (with transcranial Doppler sonography) were assessed. We found that circulating IGF-1 levels were significantly decreased with age and associated with decreased basal CBF. Age-related decline in IGF-1 levels predicted the magnitude of age-related decline in NVC responses. In conclusion, our study provides additional evidence in support of the concept that age-related circulating IGF-1 deficiency contributes to neurovascular aging, impairing CBF and functional hyperemia in older adults.

Cell non-autonomous regulation of cerebrovascular aging processes by the somatotropic axis

“…Age-related GH/IGF-1 deficiency has been causally linked to the genesis of aging phenotypes in various organ systems, including the cardiovascular system, musculoskeletal system and the central nervous system ( 95 – 105 ). Patients with decreased GH/IGF-1 have an increased risk of VCID and other forms cardiovascular and cerebrovascular disease ( 94 , 106 – 108 ), including gait and cognitive impairment ( 109 – 111 ), as well as diabetes mellitus ( 106 ). Older adults with low circulating IGF-1 levels have 39% higher risk of cardiovascular mortality ( 112 ).…”

“…IGF-1 may also play a role in regulating baseline CBF. Magnetic resonance imaging studies have shown that baseline mean blood flow velocity in the middle cerebral artery is decreased in aged vs. young cohorts, and that flow is significantly correlated with serum IGF-1 levels ( 94 ). Overall, IGF-1 has a central role in regulation of CBF by contributing to pressure- and flow-dependent responses of cerebral arteries, plays a role in structural adaptation to hypertension, and contributes to adaptive ECM changes and in ECM-related gene expression.…”

“…These preclinical studies have clinical correlates. NVC decreases in aging humans, contributing to VCID ( 94 ). In addition, recent work in aged and young study participants show that decreased serum IGF-1 levels are a significant predictor of impaired NVC responses ( 94 ).…”

“…NVC decreases in aging humans, contributing to VCID ( 94 ). In addition, recent work in aged and young study participants show that decreased serum IGF-1 levels are a significant predictor of impaired NVC responses ( 94 ). Combined, these findings highlight an essential role for IGF-1 in NVC during aging ( 105 ).…”

Role of endocrine PACAP in age-related diseases

“…Aging is a major risk factor for vascular cognitive impairment (VCI), the second most common form of cognitive impairment after AD. A wide array of functional and structural alterations of the cerebral microvasculature were shown to contribute to the pathogenesis of VCI ( 74 – 77 ) including cerebromicrovascular rarefaction ( 5 , 78 ) and a related decline in cerebral blood flow ( 79 , 80 ), microhemorrhages ( 81 – 84 ), microinfarcts ( 85 , 86 ), impaired glymphatics function ( 87 ), blood brain barrier disruption ( 88 , 89 ), consequential neuroinflammation ( 90 ), impaired neurovascular coupling ( 91 – 93 ) systemic endothelial dysfunction ( 4 , 94 ) and endothelial senescence ( 95 ). Stroke is an important consequence of cerebrovascular aging.…”