Frailty measurement in research and clinical practice: A review

Inflammation and frailty in the elderly: A systematic review and meta-analysis.

The Asia-Pacific Clinical Practice Guidelines for the Management of Frailty

Regular exercise has multi-system anti-aging effects. Here we summarize how exercise impacts the major hallmarks of aging. We propose that, besides searching for novel pharmaceutical targets of the aging process, more research efforts should be devoted to gaining insights into the molecular mediators of the benefits of exercise and to implement effective exercise interventions for elderly people.

Exercise Attenuates the Major Hallmarks of Aging

Impact of exercise training on physical and cognitive function among older adults: a systematic review and meta-analysis.

Frailty is a common and important geriatric syndrome characterized by age-associated declines in physiologic reserve and function across multiorgan systems, leading to increased vulnerability for adverse health outcomes. Two major frailty models have been described in the literature. The frailty phenotype defines frailty as a distinct clinical syndrome meeting three or more of five phenotypic criteria: weakness, slowness, low level of physical activity, self-reported exhaustion, and unintentional weight loss. The frailty index defines frailty as cumulative deficits identified in a comprehensive geriatric assessment. Significant progress has recently been made in understanding the pathogenesis of frailty. Chronic inflammation is likely a key pathophysiologic process that contributes to the frailty syndrome directly and indirectly through other intermediate physiologic systems, such as the musculoskeletal, endocrine, and hematologic systems. The complex multifactorial etiologies of frailty also include obesity and specific diseases. Major clinical applications include risk assessment and stratification. This can be applied to the elderly population in the community and in a variety of care settings. Frailty may also be useful for risk assessment in surgical patients and those with cardiovascular diseases, cancer, or human immunodeficiency virus infection, as well as for assessment of vaccine effectiveness in older adults. Currently, exercise and comprehensive geriatric interdisciplinary assessment and treatment are key interventions for frailty. As understanding of the biologic basis and complexity of frailty further improves, more effective and targeted interventional strategies and innovative geriatric-care models will likely be developed.

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Frailty syndrome: an overview

Abstract Background Neurite dystrophy is a pathologic hallmark of Alzheimer’s disease (AD). However, drug discovery targeting neurite protection in AD remains largely unexplored. Methods Aβ-induced neurite and mitochondrial damage assays were used to evaluate Aβ toxicity and the neuroprotective efficacy of a natural compound salidroside (SAL). The 5×FAD transgenic mouse model of AD was used to study the neuroprotective function of SAL. To verify the direct target of SAL, we used surface plasmon resonance and cellular thermal shift assays to analyze the drug-protein interaction. Results SAL ameliorates Aβ-mediated neurite damage in cell culture. We further reveal that SAL represses mitochondrial damage in neurites by promoting mitophagy and maintaining mitochondrial homeostasis, dependent on an NAD-dependent deacetylase SIRT3. In AD mice, SAL protects neurite morphology, mitigates Aβ pathology, and improves cognitive function, which are all SIRT3-dependent. Notably, SAL directly binds to transcription factor NRF2, inhibits its degradation by blocking its interaction with KEAP1 ubiquitin ligase, and then advances NRF2-mediated SIRT3 transcription. Conclusions Overall, we demonstrate that SAL, a potential anti-aging drug candidate, attenuates AD pathology by targeting NRF2/SIRT3 pathway for mitochondrial and neurite protection. Drug discovery strategies focusing on SAL may thus provide promising therapeutics for AD. 

/pdf/salidroside-reduces-neuropathology-in-alzheimers-disease-jxqghgcq.pdf

Salidroside reduces neuropathology in Alzheimer’s disease models by targeting NRF2/SIRT3 pathway

During liver regeneration after partial hepatectomy, the function and metabolic pathways governing transient lipid droplet accumulation in hepatocytes remain obscure. Mammalian target of rapamycin 2 (mTORC2) facilitates de novo synthesis of hepatic lipids. Under normal conditions and in tumorigenesis, decreased levels of triglyceride (TG) and fatty acids (FAs) are observed in the mTORC2-deficient liver. However, during liver regeneration, their levels increase in the absence of mTORC2.Rictor liver-specific knockout and control mice underwent partial hepatectomy, followed by measurement of TG and FA contents during liver regeneration. FA metabolism was evaluated by analyzing the expression of FA metabolism-related genes and proteins. Intraperitoneal injection of the peroxisome proliferator-activated receptor α (PPAR-α) agonist, p53 inhibitor, and protein kinase B (AKT) activator was performed to verify the regulatory pathways involved. Lipid mass spectrometry was performed to identify the potential PPAR-α activators.The expression of FA metabolism-related genes and proteins suggested that FAs are mainly transported into hepatocytes during liver regeneration. The PPAR-α pathway is down-regulated significantly in the mTORC2-deficient liver, resulting in the accumulation of TGs. The PPAR-α agonist WY-14643 rescued deficient liver regeneration and survival in mTORC2-deficient mice. Furthermore, lipidomic analysis suggested that mTORC2 deficiency substantially reduced glucosylceramide (GluCer) content. GluCer activated PPAR-α. GluCer treatment in vivo restored the regenerative ability and survival rates in the mTORC2-deficient group.Our data suggest that FAs are mainly transported into hepatocytes during liver regeneration, and their metabolism is facilitated by mTORC2 through the GluCer-PPAR-α pathway, thereby establishing a novel role for mTORC2 in lipid metabolism. 

http://www.cmghjournal.org/article/S2352345X22001692/pdf

mTORC2 Facilitates Liver Regeneration Through Sphingolipid-Induced PPAR-α-Fatty Acid Oxidation

Gracilariopsis lemaneiformis polysaccharide (GP) exerted protective effects in an aging mouse model administered with D-galactose, and its mechanism was revealed. GP increased the activity of antioxidant enzymes, reduced malondialdehyde levels in the brain and serum, alleviated D-galactose–induced damage to the liver, and ameliorated mild cognitive impairment. Abundance of the gut microbiota differed significantly between GP and control groups. GP alleviated liver and brain injuries by regulating oxidative stress and modulating the composition and metabolism of the gut microbiota.

Gracilariopsis lemaneiformis Polysaccharide Attenuates D-Galactose–Induced Aging of Mice by Regulating Oxidative Stress and Gut Microbiota


 Hepatic metabolic derangements are pivotal incidences in the occurrence of hepatic steatosis, inflammation, and fibrosis. Peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1α), a master regulator that mediates adipose metabolism and mitochondrial biogenesis, its role in hepatic steatosis and progression to steatohepatitis remains elusive. By surveying genomic data on nonalcoholic steatohepatitis (NASH) patients available in the Gene Expression Omnibus, we found that PGC-1α was significantly down-regulated compared to healthy controls, implicating the restoration of PGC-1α may ameliorate the hepatopathy. Using a hepatocyte-specific PGC-1α overexpression (LivPGC1α) mouse model, we demonstrated that PGC-1α attenuated hepatic steatosis induced by methionine-choline deficient diet (MCD). Biochemical measurements and histological examination indicated less inflammatory infiltration, collagen deposition, NF-kB activation, and less lipid accumulation in LivPGC1α liver fed MCD. Further analyses indicated that the NAD +-dependent deacetylase sirtuin 2 (SIRT2) interacted with and deacetylated PGC-1α. Congruently, ablation of SIRT2 accelerated the NASH progression in mice fed MCD, while NAD + repletion via its precursor mimicked the beneficial effect of PGC-1α overexpression and was sufficient to alleviate NASH in mice. These findings indicate that hepatic-specific overexpression of PGC-1α exerts a beneficial role in the regulation of steatohepatitis and that pharmacological activation of the SIRT2-PGC-1α-NAD + axis may help to treat NASH.

Genxiang Mao

Papers

Frailty syndrome: an overview

Salidroside reduces neuropathology in Alzheimer’s disease models by targeting NRF2/SIRT3 pathway

mTORC2 Facilitates Liver Regeneration Through Sphingolipid-Induced PPAR-α-Fatty Acid Oxidation

Gracilariopsis lemaneiformis Polysaccharide Attenuates D-Galactose–Induced Aging of Mice by Regulating Oxidative Stress and Gut Microbiota

Peroxisome proliferator-activated receptor γ coactivator 1α maintains NAD + bioavailability protecting against steatohepatitis