Aging pathobiology and therapeutics最新文献

Sleep deprivation is known to cause memory impairment and is associated with inflammation and cell damage linked to neurodegenerative diseases. GHK (glycyl-L-histidyl-L-lysine) is a naturally occurring tripeptide found in mammalian plasma. GHK has anti-inflammatory activity and can pass through the blood-brain barrier suggesting the potential to prevent neuroinflammation associated with sleep deprivation. In this study, mice were injected with 15 mg/kg GHK per day for five days and sleep deprived on the last two days of treatment. Sleep-deprived mice treated with GHK did not show the acute learning impairment seen in sleep-deprived mice treated with saline. GHK prevented an increase in MCP-1 and nitrotyrosine levels in the hippocampus of sleep-deprived mice suggesting that inflammatory and reactive nitrogen/oxygen species activity could be therapeutic targets for learning impairment associated with short-term sleep deprivation.

Cognitive impairment associated with memory loss and dysfunctional communication is a common condition in older people. Regions of the brain have been reported to decrease in size with increasing age, but the relationship with cognitive impairment is not well understood. Inbred and hybrid mouse strains can be useful models to investigate cognitive impairment and morphological changes at older ages. CB6F1 hybrid mice, a cross between C57BL/6 and Balb/c mice, were tested for learning and memory using a radial water tread maze. Old CB6F1 male mice (30 months of age) had severe cognitive impairment, while it was virtually absent in young (6 months old) male mice. In these same mice, there was a significant decrease in sagittal flat surface area of the hippocampus and pons in old versus young animals. The aging CB6F1 mouse would be a potential model to study the relationship between changes in brain morphometry and cognitive impairment and the identification of possible therapeutic targets.

A promising and novel approach for identifying anti-aging therapeutics has been the repurposing of clinically approved and readily available drugs in mice. Canagliflozin, a clinically approved safe, and effective drug for type 2 diabetic patients, was recently shown to robustly retard age-related lesions in male mice but less so in female mice. While this type of sex disparity is often seen in the field of aging, it does represent a dilemma of not knowing the cause or how translationally relevant the sex differences would be in older humans treated with Canagliflozin. Thoughtful and mechanistic investigations are needed to understand why these differences are present and whether they can be eliminated by new drugs or drug combinations. Success in using repurposed drugs for aging intervention studies in humans will depend on preclinical research to uncover pathways that can be targeted for the benefit of both sexes.

Age-related cognitive impairment (ARCI) is a neurological condition that affects millions of older people, but little is known about the increased risk of developing more severe neurodegeneration and dementia. Preclinical research is needed to understand the mechanisms of the impairment and the neuropathology associated with it. We have characterized a model of naturally occurring ARCI in the C57BL/6J mouse strain that shows an age-dependent development of cognitive impairment. As in people, some mice have little cognitive impairment while others have more severe cognitive impairment. Therefore, mice can be categorized as resistant or susceptible and the two groups can be studied for behavioral and neuropathology differences. Preliminary observations show no difference in strength and agility test scores between ARCI resistant and susceptible mice of either sex suggesting the cognitive impairment in ARCI susceptible mice is not accompanied by impairment in daily living activities, similar to ARCI in humans. The hippocampal area of the brain from ARCI susceptible mice shows evidence of an increase in the inflammatory cytokine MCP-1 compared to ARCI resistant mice, suggesting inflammation may be associated with ARCI. These preliminary observations suggest that ARCI in C57BL/6J mice could be a high-impact model to study how resilience to brain aging may predict resilience to dementia associated with Alzheimer's disease and other age-related neurological conditions.

Background: Disruption of metabolic and bioenergetic homeostasis related to mitochondrial dysfunction is a key driver of aging biology. Therefore, targeting mitochondrial function would be a rational approach to slowing aging. Elamipretide (Elam, a.k.a. SS-31) is a peptide known to target mitochondria and suppress mammalian signs of aging. The present study was designed to examine the phenotypic effects of long-term Elam treatment on aging in C57BL/6 mice starting at 18 months of age.

Methods: Mice were fed regular chow (RC diet) or a diet high in fat and sugar (HF diet) and treated with 3 mg/kg of Elam or saline subcutaneously 5 days per week for 10 months. Physiological performance assessments were conducted at 28 months of age.

Results: Elam improved the physical performance of males but not females, while in females Elam improved cognitive performance and enhanced the maintenance of body weight and fat mass. It also improved diastolic function in both males and females, but to a greater extent in males. The HF diet over 10 months had a negative effect on health span, as it increased body fat and decreased muscle strength and heart function, especially in females.

Conclusions: Elam enhanced healthy aging and cardiac function in both male and female mice, although the specific effects on function differed between sexes. In females, the treatment led to better cognitive performance and maintenance of body composition, while in males, performance on a rotating rod was preserved. These overall observations have translational implications for considering additional studies using Elam in therapeutic or preventive approaches for aging and age-related diseases.