Aging pathobiology and therapeutics最新文献

Slowing human aging with pharmaceuticals is now recognized as a feasible strategy. However, the design of clinical trials is still focused on single drug approaches. The process of aging has multiple pathways, which no current drug has been shown to effectively target. Therefore, it is of interest to study combinations, or cocktails, of drugs. A recently published article reported that a drug cocktail of rapamycin, acarbose and phenylbutyrate slowed aging in middle-aged mice treated for three months. The impact of this report is discussed, with the implications for determining endpoints in humans for testing drug cocktails as well as testing other drug combinations.

The role of IGF1R signaling in the brain and its relationship to aging and neurological dysfunction is controversial. Because it was shown that low IGF1R activity consistently improved myocardial bioenergetics and function in hearts from aging mice, but not hearts from young mice, it was of interest to investigate this relationship in brain aging. We used CRISPR technology to develop a mouse model with targeted replacement of mouse IGF1R with the equivalent of the human R407H (IGF1R^R407H) variant enriched in centenarians with a reduction in IGF1R protein activity. Middle-aged mice show improved cognitive performance thus possibly modeling IGF1R signaling in the aging brain, similar to what was reported in the aging heart. Because Alzheimer's disease (AD) is an age-related disease, specific IGF1R^R407H pathways could be therapeutic targets in mice with AAV vector-based AD as well as for overall brain aging.

Accumulating evidence suggests there is an alternative insulin transporter besides the insulin receptor at the blood-brain barrier (BBB), responsible for shuttling insulin from the circulation into the brain. In this review, we summarize key features of the BBB and what makes it unique compared to other capillary beds; summarize what we know about insulin BBB transport; provide an extensive list of diseases, physiological states, and serum factors tested in modifying insulin BBB transport; and lastly, highlight potential alternative transport systems that may be involved in or have already been tested in mediating insulin BBB transport. Identifying the transport system for insulin at the BBB would aide in controlling central nervous system (CNS) insulin levels in multiple diseases and conditions including Alzheimer's disease (AD) and obesity, where availability of insulin to the CNS is limited.

The descriptive term "normal" aging is often used in scientific literature to indicate commonly occurring changes with increasing age in the absence of overt disease. However, significant molecular and geropathological changes are increasingly present to indicate there is nothing normal about aging. Thus, the term "normal" aging is scientifically incorrect. There are changes in multiple genetic and epigenetic processes and pathways that drive aging, and some individuals are more resilient to these changes than others. Thus, "resilient" aging would be a more correct term to represent a major emphasis on investigating mechanisms and therapeutic targets for resilience, rather than a label of "normal" aging that is misleading and currently receives relatively little attention.

Background: Multimorbidity is a public health concern and an essential component of aging and healthspan but understudied because investigative tools are lacking that can be translatable to capture similarities and differences of the aging process across species and variability between individuals and individual organs.

Methods: To help address this need, body organ disease number (BODN) borrowed from human studies was applied to C57BL/6 (B6) and CB6F1 mouse strains at 8, 16, 24, and 32 months of age, as a measure of systems morbidity based on pathology lesions to develop a mouse PathoClock resembling clinically-based Body Clock in humans, using Bayesian inference. A mouse PhysioClock was also developed based on measures of physiological domains including cardiovascular, neuromuscular, and cognitive function in the same two mouse strains so that alignment with BODN was predictable.

Results: Between- and within-age variabilities in PathoClock and PhysioClock, as well as between-strain variabilities. Both PathoClock and PhysioClock correlated with chronological age more strongly in CB6F1 than C57BL/6. Prediction models were then developed, designated as PathoAge and PhysioAge, using regression models of pathology and physiology measures on chronological age. PathoAge better predicted chronological age than PhysioAge as the predicted chronological and observed chronological age for PhysioAge were complex rather than linear.

Conclusion: PathoClock and PhathoAge can be used to capture biological changes that predict BODN, a metric developed in humans, and compare multimorbidity across species. These mouse clocks are potential translational tools that could be used in aging intervention studies.

Old cats develop chronic diseases similar to diseases in older people. One-fourth of American households own cats, and almost half are more than 7 years old. Cats share the same environment and are exposed to many of the same chemical stresses. In addition, genomic diversity and population stratification are similar to that occurring in people. With these comparative features, the aging cat represents a geroscience model to investigate the pathogenesis and therapeutic interventions for aging. However, cats are generally not recognized as a translational model for aging research mainly because of the lack of knowledge and appreciation within the scientific community. In addition, cat owners are not aware of any research programs designed to enhance healthy aging in their pets because none exist. Much work is needed to inform and educate the scientific community as well as cat owners about the power of aging cats as a transformative model to investigate aging and age-related diseases that will benefit both human and feline health.

Anxiety disorders are common in older adults and are strongly associated with increased risk for numerous age-related conditions. Preclinical mechanistic data are needed to identify more specific therapeutic targets for treating and preventing these disorders. Mice serve as excellent preclinical models as they have been used extensively in aging studies, and behavioral tests have been developed. A panel of tests would capture the important clinical aspects of apathy, anxiety, and psychomotor behavior and allow longitudinal testing strategies in a rigorous and minimally stressful manner.

Acarbose (Acb) is an antidiabetic drug used to reduce blood glucose by inhibiting the conversion of complex carbohydrates into simple sugars. It has also shown promise as an anti-aging drug by increasing lifespan in mice but studies have not been reported on the effects of short-term treatment in aging mice. To address this question, 20-month-old C57BL/6 male and female mice were given a standard diet, or a diet supplemented with 1000 ppm Acb for 3 months. After this period, mice were assessed for age-related lesions as readouts for the delay in the progression of aging. Results showed there was a significant decrease in lesions of the heart and kidney in mice treated with Acb suggesting that Acb can suppress cardiac and renal pathology associated with increasing age.

Loss of physical performance, as seen in humans by decreased grip strength and overall physical fitness, is generally accepted to be a consequence of aging. Treatments to delay or reduce these changes or increase resilience to them are generally not available. In this preliminary study, 20-month-old male and female C57BL/6 mice were given either a standard mouse diet or a formulated mouse diet containing rapamycin (14 ppm), acarbose (1000 ppm), and phenylbutyrate (1000 ppm), or a diet containing one half dose of each drug, for 3 months. At the end of the study, performance on a rotarod and grip strength test was compared. In general, mice fed the full dose drug cocktail diet performed better on these assays, with significant improvements in rotarod performance in females fed the full dose cocktail and in grip strength in males fed the full dose cocktail, and females fed the low dose cocktail. These observations provide support for the concept that short term treatment with a cocktail of drugs that targets multiple aging pathways can increase resilience to aging, and suggests that this prototype cocktail could be part of a clinical therapeutic strategy for delaying age-related loss of physical performance in people.