Insulin-like growth factor-1 in CNS and cerebrovascular aging

Insulin-like growth factor-1 (IGF-1) is an important anabolic hormone that decreases with age. In the past two decades, extensive research has determined that the reduction in IGF-1 is an important component of the age-related decline in cognitive function in multiple species including humans. Deficiency in circulating IGF-1 results in impairment in processing speed and deficiencies in both spatial and working memory. Replacement of IGF-1 or factors that increase IGF-1 to old animals and humans reverses many of these cognitive deficits. Despite the overwhelming evidence for IGF-1 as an important neurotrophic agent, the specific mechanisms through which IGF-1 acts have remained elusive. Recent evidence indicates that IGF-1 is both produced by and has important actions on the cerebrovasculature as well as neurons and glia. Nevertheless, the specific regulation and actions of brain- and vascular-derived IGF-1 is poorly understood. The diverse effects of IGF-1 discovered thus far reveal a complex endocrine and paracrine system essential for integrating many of the functions necessary for brain health. Identification of the mechanisms of IGF-1 actions will undoubtedly provide critical insight into regulation of brain function in general and the causes of cognitive decline with age

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

Age-related cerebrovascular pathologies, ranging from cerebromicrovascular functional and structural alterations to large vessel atherosclerosis, promote the genesis of vascular cognitive impairment and dementia (VCID) and exacerbate Alzheimer’s disease. Recent advances in geroscience, including results from studies on heterochronic parabiosis models, reinforce the hypothesis that cell non-autonomous mechanisms play a key role in regulating cerebrovascular aging processes. Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) exert multifaceted vasoprotective effects and production of both hormones is significantly reduced in aging. This brief overview focuses on the role of age-related GH/IGF-1 deficiency in the development of cerebrovascular pathologies and VCID. It explores the mechanistic links among alterations in the somatotropic axis, specific macrovascular and microvascular pathologies (including capillary rarefaction, microhemorrhages, impaired endothelial regulation of cerebral blood flow, disruption of the blood brain barrier, decreased neurovascular coupling, and atherogenesis) and cognitive impairment. Improved understanding of cell non-autonomous mechanisms of vascular aging is crucial to identify targets for intervention to promote cerebrovascular and brain health in older adults

Influence of diabetes on ambulation and inflammation in men and women with symptomatic peripheral artery disease

AbstractObjectiveTo determine whether diabetes and sex were factors associated with ambulatory function, endothelial cell inflammation, oxidative stress, and apoptosis, and with circulating biomarkers of inflammation and antioxidant capacity in patients with peripheral artery disease (PAD) and claudication.Materials/MethodsAmbulatory function of 180 symptomatic men and women with PAD was assessed during a graded maximal treadmill test, 6-minute walk test, and 4-meter walk test. Patients were further characterized on endothelial effects of circulating factors present in the sera using a cell culture-based bioassay on primary human arterial endothelial cells, and on circulating inflammatory and vascular biomarkers.ResultsMen and women with diabetes had greater prevalence (p = 0.007 and p = 0.015, respectively) of coronary artery disease (CAD) than patients without diabetes. To assure that this difference did not influence planned comparisons, the data set was stratified on CAD. Diabetic men with CAD had a lower peak walking time (PWT) during the treadmill test and a slower 4-meter gait speed compared to non-diabetic men with CAD (p < 0.05). Diabetic women with CAD had a lower PWT compared to their non-diabetic counterparts (p < 0.01). Additionally, diabetic men with CAD had higher pigment epithelium-derived factor (p < 0.05) than their non-diabetic counterparts, and diabetic women with CAD had higher leptin (p < 0.01) and interleukin-8 levels (p < 0.05).ConclusionsIn patients with PAD, diabetic men and women with CAD had more severe claudication than their non-diabetic counterparts, as measured by shorter PWT, and the men had further ambulatory impairment manifested by slower 4-meter gait speed. Furthermore, the diabetic patients with CAD had elevations in interleukin-8, leptin, and PEDF

Resveratrol Supplementation Confers Neuroprotection in Cortical Brain Tissue of Nonhuman Primates Fed a High-Fat/Sucrose Diet

Previous studies have shown positive effects of long-term resveratrol (RSV) supplementation in preventing pancreatic beta cell dysfunction, arterial stiffening and metabolic decline induced by high-fat/high-sugar (HFS) diet in nonhuman primates. Here, the analysis was extended to examine whether RSV may reduce dietary stress toxicity in the cerebral cortex of the same cohort of treated animals. Middle-aged male rhesus monkeys were fed for 2 years with HFS alone or combined with RSV, after which whole-genome microarray analysis of cerebral cortex tissue was carried out along with ELISA, immunofluorescence, and biochemical analyses to examine markers of vascular health and inflammation in the cerebral cortices. A number of genes and pathways that were differentially modulated in these dietary interventions indicated an exacerbation of neuroinflammation (e.g., oxidative stress markers, apoptosis, NF-κB activation) in HFS-fed animals and protection by RSV treatment. The decreased expression of mitochondrial aldehyde dehydrogenase 2, dysregulation in endothelial nitric oxide synthase, and reduced capillary density induced by HFS stress were rescued by RSV supplementation. Our results suggest that long-term RSV treatment confers neuroprotection against cerebral vascular dysfunction during nutrient stress

Expanding the horizon of research into the pathogenesis of the white matter diseases: Proceedings of the 2021 Annual Workshop of the Albert Research Institute for White Matter and Cognition

White matter pathologies are critically involved in the etiology of vascular cognitive impairment–dementia (VCID), Alzheimer’s disease (AD), and Alzheimer’s disease and related diseases (ADRD), and therefore need to be considered a treatable target (Roseborough A, Hachinski V, Whitehead S. White matter degeneration - a treatable target? Roseborough et al. JAMA Neurol [Internet]. 2020 Apr 27;77(7):793–4, [1]. To help address this often-missed area of research, several workshops have been sponsored by the Leo and Anne Albert Charitable Trust since 2015, resulting in the incorporation of “The Albert Research Institute for White Matter and Cognition” in 2020. The first annual “Institute” meeting was held virtually on March 3–4, 2021. The Institute provides a forum and workspace for communication and support of the advancement of white matter science and research to better understand the evolution and prevention of dementia. It serves as a platform for young investigator development, to introduce new data and debate biology mechanisms and new ideas, and to encourage and support new research collaborations and directions to clarify how white matter changes, with other genetic and health risk factors, contribute to cognitive impairment. Similar to previous Albert Trust–sponsored workshops (Barone et al. in J Transl Med 14:1–14, [2]; Sorond et al. in GeroScience 42:81–96, [3]), established expert investigators were identified and invited to present. Opportunities to attend and present were also extended by invitation to talented research fellows and younger scientists. Also, updates on institute-funded research collaborations were provided and discussed. The summary that follows is a synopsis of topics and discussion covered in the workshop

Role of NAD(P)H Oxidase in Superoxide Generation and Endothelial Dysfunction in Goto-Kakizaki (GK) Rats as a Model of Nonobese NIDDM

Background: Cardiovascular disease is the leading cause of mortality in diabetics, and it has a complex etiology that operates on several levels. Endothelial dysfunction and increased generation of reactive oxygen species are believed to be an underlying cause of vascular dysfunction and coronary artery disease in diabetes. This impairment is likely the result of decreased bioavailability of nitric oxide (NO) within the vasculature. However, it is unclear whether hyperglycemia per se stimulates NADPH oxidase-derived superoxide generation in vascular tissue. Methods and Results: This study focused on whether NADPH oxidase-derived superoxide is elevated in vasculature tissue evoking endothelial/smooth muscle dysfunction in the hyperglycemic (16964 mg%) Goto-Kakizaki (GK) rat. By dihydroethidine fluorescence staining, we determined that aorta superoxide levels were significantly elevated in 9 month-old GK compared with age matched Wistar (GK; 19566%, Wistar; 10063.5%). Consistent with these findings, 10 26 mol/L acetylcholine-induced relaxation of the carotid artery was significantly reduced in GK rats compared with age matched Wistar (GK; 4167%, Wistar; 10065%) and measurements in the aorta showed a similar trend (p =.08). In contrast, relaxation to the NO donor SNAP was unaltered in GK compared to Wistar. Endothelial dysfunction was reversed by lowering of superoxide with apocynin, a specific Nox inhibitor. Conclusions: The major findings from this study are that chronic hyperglycemia induces significant vascular dysfunction i

New species longevity record for the northern quahog (=hard clam), Mercenaria mercenaria

Author Posting. © National Shellfisheries Association, 2011. This article is posted here by permission of National Shellfisheries Association for personal use, not for redistribution. The definitive version was published in Journal of Shellfish Research 30 (2011): 35-38, doi:10.2983/035.030.0106.Twenty-two large shells (>90 mm shell height) from a sample of live collected hard shell clams, Mercenaria mercenaria, from Buzzards Bay, Woods Hole, Cape Cod, MA, were subjected to sclerochronological analysis. Annually resolved growth lines in the hinge region and margin of the shell were identified and counted; the age of the oldest clam shell was determined to be at least 106 y. This age represents a considerable increase in the known maximum life span for M. mercenaria, more than doubling the maximum recorded life span of the species (46 y). More than 85% of the clam shells aged had more than 46 annual increments, the previous known maximum life span for the species. In this article we present growth rate and growth performance indicators (the overall growth performance and phi prime) for this record-breaking population of M. mercenaria. Recently discovered models of aging require accurate age records and growth parameters for bivalve populations if they are to be utilized to their full potential.This work was supported by grants from the American Diabetes Association (to Z. U.), American Federation for Aging Research (to A. C.), the University of Oklahoma College of Medicine Alumni Association (to A. C.), the BBSRC (to C. A. R.),the National Institutes of Health (AT006526 and HL077256 to Z. U.; AG022873 and AG025063 to S. N. A.), and the DFG Cluster of Excellence ‘‘Future Ocean’’ (to E. P.)

Nicotinamide mononucleotide (NMN) supplementation promotes anti-aging miRNA expression profile in the aorta of aged mice, predicting epigenetic rejuvenation and anti-atherogenic effects

Understanding molecular mechanisms involved in vascular aging is essential to develop novel interventional strategies for treatment and prevention of age-related vascular pathologies. Recent studies provide critical evidence that vascular aging is characterized by NAD+ depletion. Importantly, in aged mice, restoration of cellular NAD+ levels by treatment with the NAD+ booster nicotinamide mononucleotide (NMN) exerts significant vasoprotective effects, improving endothelium-dependent vasodilation, attenuating oxidative stress, and rescuing age-related changes in gene expression. Strong experimental evidence shows that dysregulation of microRNAs (miRNAs) has a role in vascular aging. The present study was designed to test the hypothesis that age-related NAD+ depletion is causally linked to dysregulation of vascular miRNA expression. A corollary hypothesis is that functional vascular rejuvenation in NMN-treated aged mice is also associated with restoration of a youthful vascular miRNA expression profile. To test these hypotheses, aged (24- month-old) mice were treated with NMN for 2 weeks and miRNA signatures in the aortas were compared to those in aortas obtained from untreated young and aged control mice. We found that protective effects of NMN treatment on vascular function are associated with anti-aging changes in the miRNA expression profile in the aged mouse aorta. The predicted regulatory effects of NMN-induced differentially expressed miRNAs in aged vessels include anti-atherogenic effects and epigenetic rejuvenation. Future studies will uncover the mechanistic role of miRNA gene expression regulatory networks in the anti-aging effects of NAD+ booster treatments and determine the links between miRNAs regulated by NMN and sirtuin activators and miRNAs known to act in the conserved pathways of aging and major aging-related vascular diseases

Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction without Extending Life Span

22 páginas, 4 figuras.A small molecule that safely mimics the ability of dietary restriction (DR) to delay age-related diseases in laboratory animals is greatly sought after. We and others have shown that resveratrol mimics effects of DR in lower organisms. In mice, we find that resveratrol induces gene expression patterns in multiple tissues that parallel those induced by DR and every-other-day feeding. Moreover, resveratrol-fed elderly mice show a marked reduction in signs of aging, including reduced albuminuria, decreased inflammation, and apoptosis in the vascular endothelium, increased aortic elasticity, greater motor coordination, reduced cataract formation, and preserved bone mineral density. However, mice fed a standard diet did not live longer when treated with resveratrol beginning at 12 months of age. Our findings indicate that resveratrol treatment has a range of beneficial effects in mice but does not increase the longevity of ad libitum-fed animals when started midlife.This work was supported by grants from the American Heart Association (0425834T to J.A.B. and 0435140N to A.C.) and from the NIH (RO1GM068072, AG19972, and AG19719 to D.A.S.), (HL077256 to Z.U.), (HD034089 to L.W), (2RO1 EY011733 to N.S.W.), Spanish grant (BFU2005-03017 to P.N.), and by the generous support of Mr. Paul F. Glenn and The Paul F. Glenn Laboratories for the Biological Mechanisms of Aging.Peer reviewe

SRT1720 improves survival and healthspan of obese mice

Sirt1 is an NAD+-dependent deacetylase that extends lifespan in lower organisms and improves metabolism and delays the onset of age-related diseases in mammals. Here we show that SRT1720, a synthetic compound that was identified for its ability to activate Sirt1 in vitro, extends both mean and maximum lifespan of adult mice fed a high-fat diet. This lifespan extension is accompanied by health benefits including reduced liver steatosis, increased insulin sensitivity, enhanced locomotor activity and normalization of gene expression profiles and markers of inflammation and apoptosis, all in the absence of any observable toxicity. Using a conditional SIRT1 knockout mouse and specific gene knockdowns we show SRT1720 affects mitochondrial respiration in a Sirt1- and PGC-1α-dependent manner. These findings indicate that SRT1720 has long-term benefits and demonstrate for the first time the feasibility of designing novel molecules that are safe and effective in promoting longevity and preventing multiple age-related diseases in mammals