Aging pathobiology and therapeutics最新文献

Genetic variation does not entirely address the consistent divergence of healthy and unhealthy aging in heterogeneous and homogeneous mammalian populations. The alteration of gene function through modification of histone DNA infrastructure is a logical extending explanation for this divergence. Since epigenetic alterations are reversible, therapeutic interventions that target the right gene or gene products could reverse aging, at the very least in the population of older people with poor health.

Hepatic steatosis, also known as fatty liver, is a spontaneous lesion caused by the abnormal accumulation of triglycerides within hepatocytes that has been described in different laboratory-housed nonhuman primate species. Aging is considered a risk factor in the progression of this lesion in humans and captive rhesus macaques. Hepatic steatosis has been reported in sexually mature adult and aged-adult captive common marmosets. Macroscopic changes in the liver may be evident in advanced stages of this condition and are characterized by hepatomegaly with multifocal to coalescing to regionally extensive pale-tan to yellow, soft foci throughout the hepatic lobes. Biochemical abnormalities in these cases include significantly increased levels in triglycerides, insulin, and γ-glutamyltransferase (GGT). Definitive diagnosis is by histopathology and demonstration of lipid accumulation within hepatocytes. Histopathology is characterized by large coalescing areas of periacinar to periportal microvesicular steatosis mixed with clusters of macrovesicular steatosis, and variable degrees of lobular inflammation. Vacuolated hepatocytes containing intracytoplasmic lipid material is demonstrated by positive staining to Sudan IV and/or Oil red-O.

The ability to respond to stress, defined as resilience, was measured by white blood cell counts in C57BL/6 mice of various ages receiving a nonlethal dose of cyclophosphamide (CYP). Neutrophil counts dipped and then rebounded in a consistent and age-dependent manner. Low neutrophil rebound correlated with improved learning in middle-age mice suggesting CYP-nduced neutrophil response may predict resilience to aging.

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.

Effective treatments to prevent or delay age-related learning impairment are not generally available. In a preliminary preclinical study, mice 20 months of age were fed a diet containing 14 ppm rapamycin, an inhibitor of mTOR, for three months and then tested in a spatial navigation task. Mice fed the nonmedicated control diet showed learning impairment while mice fed the rapamycin diet were not learning impaired. This observation provides support for additional preclinical studies and suggests that short-term rapamycin treatment could be a possible strategy for preventing or delaying age-related cognitive impairment in people.

The idea that the degree of response to physical stress in early life can be used to measure health in later life is a novel approach to better define resilience to aging. To investigate this, middle-age (15 months) mice were stressed by vaccination with a commercial pneumococcal vaccine (Prevnar 13), and 30 days later separated into a high antibody response group and a low antibody response group using Elisa to detect IgG serum antibody levels. After 4 months, mice were evaluated for physiological performance and learning ability. The high antibody response group was able to stay on a rotating rod longer than the low antibody response group and were more quickly able to find the escape hole in a spatial navigation learning task. This observation suggests Prevnar 13 antibody response in midlife could be a useful stress test to predict healthy aging.

Translational research regularly utilizes immunohistochemistry (IHC) to investigate pathological differences in the clinical or laboratory setting. However, the majority of these studies require the extensive work of a trained pathologist to analyze slides in a meaningful way. In order to explore new ways to quantitate IHC stains in a manner that is reproducible and efficient for both pathologists and research scientists, QuPath was explored as a new digital imaging tool. The hippocampal area of brains from older sleep deprived mice were stained using established IHC protocols to explore biomarker levels that would be insightful for measurable differences. Application features of QuPath are described that quantitatively show sleep deprived mice had robust differences in staining intensity for four different biomarkers compared to non-sleep deprived mice. These observations provide the rationale for QuPath as a digital imaging tool to enhance the quantitative and qualitative usefulness of IHC staining in the field of geropathology.

GHK (glycyl-L-histidyl-L-lysine) is a naturally occurring peptide found in human serum with levels averaging 200 ng/ml at age 20 but declining to an average of 80 ng/ml by age 60. The molecule has a very high affinity for copper and forms the chelate GHK-Cu. The peptide as well as its Cu (II) chelate have anti-inflammatory and tissue remodeling properties. GHK-Cu has been shown to promote skin remodeling, wound healing and regeneration, and has prominent antioxidant and anti-inflammatory effects in in vitro and in vivo studies. In addition, preliminary observations suggest GHK can partially reverse cognitive impairment in aging mice by targeting anti-inflammatory and epigenetic pathways. The evidence as presented provides the rationale to further investigate this naturally occurring peptide in preclinical and clinical aging studies.

Background: Apc ^Min/+ mice model familial adenomatous polyposis (FAP), a disease that causes numerous colon polyps leading to colorectal cancer. We previously showed that chronic treatment of Apc ^Min/+ females with the anti-aging drug, rapamycin, restored a normal lifespan through reduced polyposis and anemia prevention. Lifespan extension by chronic rapamycin in wildtype UM-HET3 mice is sex-dependent with females gaining the most benefit. Whether Apc ^Min/+ mice have a similar sex-dependent response to chronic mTOR inhibition is not known.

Methods: To address this knowledge gap and gain deeper insight into how chronic mTOR inhibition prevents intestinal polyposis, we compared male and female Apc ^Min/+ mice responses to chronic treatment with a rapamycin-containing diet. Animals were fed a diet containing either 42 ppm microencapsulate rapamycin or empty capsules, one group was used to determine lifespan and a second group with similar treatment was harvested at 16 weeks of age for cross-sectional studies.

Results: We found that the survival of males is greater than females in this setting (P < 0.0197). To explore the potential basis for this difference we analyzed factors affected by chronic rapamycin. Immunoblot assays showed that males and females exhibited approximately the same level of mTORC1 inhibition using phosphorylation of ribosomal protein S6 (rpS6) as an indirect measure. Immunohistochemistry assays of rpS6 phosphorylation showed that rapamycin reduction of mTORC1 activity was on the same level, with the most prominent difference being in intestinal crypt Paneth cells in both sexes. Chronic rapamycin also reduced crypt depths in both male and female Apc ^Min/+ mice (P < 0.0001), consistent with reduced crypt epithelial cell proliferation. Finally, chronic rapamycin prevented anemia equally in males and females.

Conclusions: In males and females, these findings link rapamycin-mediated intestinal polyposis prevention with mTORC1 inhibition in Paneth cells and concomitant reduced epithelial cell proliferation.

A geropathology grading platform (GGP) for assessing age-related lesions has been established and validated for in inbred strain of mice. Because nonhuman primates (NHPs) share significant similarities in aging and spontaneous chronic diseases with humans, they provide excellent translational value for correlating histopathology with biological and pathological events associated with increasing age. Descriptive age-associated pathology has been described for rhesus macaques and marmosets, but a grading platform similar to the mouse GGP does not exist. The value of these NHP models is enhanced by considerable historical data from clinical, bio-behavioral, and social domains that align with health span in these animals. Successful adaptation of the mouse GGP for NHPs will include 1) expanding the range of organs examined; 2) standardizing necropsy collection, tissue trimming, and descriptive lesion terminology; 3) expanding beyond rhesus macaques and marmosets to include other commonly used NHPs in research; and 4) creating a national resource for age-related pathology to complement the extensive in-life datasets. Adaptation of the GGP to include translational models other than mice will be crucial to advance geropathology designed to enhance aging research.