A drug cocktail of rapamycin, acarbose, and phenylbutyrate enhances resilience to features of early-stage Alzheimer's disease in aging mice.

The process of aging is defined by the breakdown of critical maintenance pathways leading to an accumulation of damage and its associated phenotypes. Aging affects many systems and is considered the greatest risk factor for a number of diseases. Therefore, interventions aimed at establishing resilience to aging should delay or prevent the onset of age-related diseases. Recent studies have shown a three-drug cocktail consisting of rapamycin, acarbose, and phenylbutyrate delayed the onset of physical, cognitive, and biological aging phenotypes in old mice. To test the ability of this drug cocktail to impact Alzheimer's disease (AD), an adeno-associated-viral vector model of AD was created. Mice were fed the drug cocktail 2 months prior to injection and allowed 3 months for phenotypic development. Cognitive phenotypes were evaluated through a spatial navigation learning task. To quantify neuropathology, immunohistochemistry was performed for AD proteins and pathways of aging. Results suggested the drug cocktail was able to increase resilience to cognitive impairment, inflammation, and AD protein aggregation while enhancing autophagy and synaptic integrity, preferentially in female cohorts. In conclusion, female mice were more susceptible to the development of early stage AD neuropathology and learning impairment, and more responsive to treatment with the drug cocktail in comparison to male mice. Translationally, a model of AD where females are more susceptible would have greater value as women have a greater burden and incidence of disease compared to men. These findings validate past results and provide the rationale for further investigations into enhancing resilience to early-stage AD by enhancing resilience to aging.

Behavioral and neuropathological features of Alzheimer's disease are attenuated in 5xFAD mice treated with intranasal GHK peptide.

Efforts to find disease modifying treatments for Alzheimer's disease (AD) have met with limited success in part because the focus has been on testing drugs that target a specific pathogenic mechanism. Multiple pathways have been implicated in the pathogenesis of AD. Hence, the probability of more effective treatment for AD is likely increased by using an intervention that targets more than one pathway. The naturally occurring peptide GHK (glycyl-L-histidyl-L-lysine), as a GHK-Cu complex, supports angiogenesis, remodeling, and tissue repair, has anti-inflammatory and antioxidant properties, and has been shown to improve cognitive performance in aging mice. In order to test GHK-Cu as a neurotherapeutic for AD, male and female 5xFAD transgenic mice on the C57BL/6 background at 4 months of age were given 15 mg/kg GHK-Cu intranasally 3 times per week for 3 months until 7 months of age. Results showed that intranasal GHK-Cu treatment delayed cognitive impairment, reduced amyloid plaques, and lowered inflammation levels in the frontal cortex and hippocampus. These observations suggest additional studies are warranted to investigate the potential of GHK-Cu peptide as a promising treatment for AD.

Intranasal GHK peptide enhances resilience to cognitive decline in aging mice.

Brain aging and cognitive decline are aspects of growing old. Age-related cognitive impairment entails the early stages of cognitive decline, and is extremely common, affecting millions of older people. Investigation into early cognitive decline as a treatable condition is relevant to a wide range of cognitive impairment conditions, since mild age-related neuropathology increases risk for more severe neuropathology and dementia associated with Alzheimer's Disease. Recent studies suggest that the naturally occurring peptide GHK (glycyl-L-histidyl-L-lysine) in its Cu-bound form, has the potential to treat cognitive decline associated with aging. In order to test this concept, male and female C57BL/6 mice, 20 months of age, were given intranasal GHK-Cu, 15 mg/kg daily, for two months. Results showed that mice treated with intranasal GHK-Cu had an enhanced level of cognitive performance in spatial memory and learning navigation tasks, and expressed decreased neuroinflammatory and axonal damage markers compared to mice treated with intranasal saline. These observations suggest that GHK-Cu can enhance resilience to brain aging, and has translational implications for further testing in both preclinical and clinical studies using an atomizer device for intranasal delivery.

Older-aged C57BL/6 mice fed a diet high in saturated fat and sucrose for ten months show decreased resilience to aging.

The ability to respond to physical stress that disrupts normal physiological homeostasis at an older age embraces the concept of resilience to aging. A physical stressor could be used to induce physiological responses that are age-related, since resilience declines with increasing age. Increased fat and sugar intake is a nutritional stress with a high prevalence of obesity in older people. In order to determine the effect of this type of diet on resilience to aging, 18-month-old C57BL/6J male mice were fed a diet high in saturated fat (lard) and sucrose (HFS) for ten months. At the end of the 10-month study, mice fed the HFS diet showed increased cognitive impairment, decreased cardiac function, decreased strength and agility, and increased severity of renal pathology compared to mice fed a rodent chow diet low in saturated fat and sucrose (LFS). The degree of response aligned with decreased resilience to the long-term adverse effects of the diet with characteristics of accelerated aging. This observation suggests additional studies could be conducted to investigate the relationship between an accelerated decline in resilience to aging and enhanced resilience to aging under different dietary conditions.

Long-term treatment with Elamipretide enhances healthy aging phenotypes in mice.

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.

Short term treatment with a cocktail of rapamycin, acarbose and phenylbutyrate delays aging phenotypes in mice.

Pharmaceutical intervention of aging requires targeting multiple pathways, thus there is rationale to test combinations of drugs targeting different but overlapping processes. In order to determine if combining drugs shown to extend lifespan and healthy aging in mice would have greater impact than any individual drug, a cocktail diet containing 14 ppm rapamycin, 1000 ppm acarbose, and 1000 ppm phenylbutyrate was fed to 20-month-old C57BL/6 and HET3 4-way cross mice of both sexes for three months. Mice treated with the cocktail showed a sex and strain-dependent phenotype consistent with healthy aging including decreased body fat, improved cognition, increased strength and endurance, and decreased age-related pathology compared to mice treated with individual drugs or control. The severity of age-related lesions in heart, lungs, liver, and kidney was consistently decreased in mice treated with the cocktail compared to mice treated with individual drugs or control, suggesting an interactive advantage of the three drugs. This study shows that a combination of three drugs, each previously shown to enhance lifespan and health span in mice, is able to delay aging phenotypes in middle-aged mice more effectively than any individual drug in the cocktail over a 3-month treatment period.

A model for studying cutaneous wound healing and resilience to aging: Ear punch biopsy in old mice.

Resilience to aging is a biological event that precedes age-related decline in physiological function and is defined as an organism's ability to respond to physical stress with increasing age. There is a need to identify factors that may predict resilience for enhancing and maintaining healthy aging. Older people often experience delayed wound healing beause of compromised tissue repair and immune response. Therefore preclincal models may be of value to investigate the relationship between cutaneous wound healing and resilience to aging. This brief report descibes an ear punch biopsy model of cutaneous wound healing in aging mice and shows that mice with biopsy ear wounds that heal more quickly have better cognition, increased strength and better running endurance later in life.

Curcumin suppresses intestinal polyps in APC Min mice fed a high fat diet.

Colorectal cancer (CRC) is a leading cause of cancer deaths in the United States. Various risk factors have been associated with CRC including increasing age and diet. Epidemiological and experimental studies have implicated a diet high in fat as an important risk factor for colon cancer. High fat diets can promote obesity resulting in insulin resistance and inflammation and the development of oxidative stress, increased cell proliferation, and suppression of apoptosis. Because of the high consumption of dietary fats, especially saturated fats, by Western countries, it is of interest to see if non-nutrient food factors might be effective in preventing or delaying CRC in the presence of high saturated fat intake. Curcumin (Curcuma longa), the main yellow pigment in turmeric, was selected to test because of its reported anti-tumor activity. APC Min mice, which develop intestinal polyps and have many molecular features of CRC, were fed a diet containing 35% pork fat, 33% sucrose, and a protein and vitamin mineral mixture (HFD) with or without 0.5% curcumin. These cohorts were compared to APC Min mice receiving standard rodent chow (RC) with 8% fat. APC Min mice fed the HFD for 3 months had a 23% increase in total number of polyps compared to APC Min mice on RC. Curcumin was able to significantly reverse the accelerated polyp development associated with the HFD suggesting it may be effective clinically in helping prevent colon cancer even when ingesting high amounts of fatty foods. The anti-tumor effect of curcumin was shown to be associated with enhanced apoptosis and increased efficiency of DNA repair. Since curcumin prevented the gain in body weight seen in APC Min mice ingesting the HFD, modulation of energy metabolism may also be a factor.

Attenuation of age-related metabolic dysfunction in mice with a targeted disruption of the Cbeta subunit of protein kinase A.

The cyclic adenosine monophosphate-dependent protein kinase A (PKA) pathway helps regulate both cell growth and division, and triglyceride storage and metabolism in response to nutrient status. Studies in yeast show that disruption of this pathway promotes longevity in a manner similar to caloric restriction. Because PKA is highly conserved, it can be studied in mammalian systems. This report describes the metabolic phenotype of mice lacking the PKA catalytic subunit Cbeta. We confirmed that Cbeta has high levels of expression in the brain but also showed moderate levels in liver. Cbeta-null animals had reduced basal PKA activity while appearing overtly normal when fed standard rodent chow. However, the absence of Cbeta protected mice from diet-induced obesity, steatosis, dyslipoproteinemia, and insulin resistance, without any differences in caloric intake or locomotor activity. These findings have relevant pharmacological implications because aging in mammals is characterized by metabolic decline associated with obesity, altered body fat distribution, and insulin resistance.