Biological age generally occurs earlier or later than chronological age and can be used as a biomarker for aging intervention studies. The rate of wound healing is known to decrease with increasing age, such that a simple skin wound might demonstrate overall aging of all organs and tissues of the body. This concept was tested in a mouse model of wound healing consisting of a 2 mm through and through ear biopsy. Cohorts of male and female C57BL/6 mice at 5, 13, and 21 months of age were biopsied, and the area of closure measured over 3 weeks. Ear biopsy cores were used to obtain DNA methylation signatures to a database of age-related signatures to compare biological age. The 5-month-old mice showed a higher percentage of wound healing than the 21-month-old mice 2.5 weeks following the biopsy with a p-value of 0.04. DNA methylation results used to calculate expected wound healing percentage correlated with measured healing percentage with an R2 value of 0.82. Additional validation of biological age will use a computational paradigm to assess severity of age-related lesions on an inter and intra-organ basis. Preliminary observations from this study indicate that a simple skin biopsy procedure can be used to predict biological age, with important translational implications for the treatment and prevention of aging and age-related diseases.

Alzheimer’s disease (AD) is a complex neurodegenerative condition that commonly affects aged populations; therefore, increasing resilience to aging may increase resilience to age-related diseases including AD. To test this concept, a preclinical mouse study was designed to investigate the effects of anti-aging drugs rapamycin, acarbose, and phenylbutyrate in combination (cocktail) previously shown to delay aging phenotypes in mice. Cohorts of C57BL/6 mice, 22 months of age and of both sexes, were fed standard chow containing the drug cocktail or standard control chow for two months. Mice were then given an intravenous injection of a neuronal-specific adeno-associated virus (AAV) vector consisting of Aβ and phosphorylated (p) tau, the major pathogenic components of AD, or AAV sham, and followed for another three months. Mice were then tested for cognitive function using a spatial navigation learning task. Overall, AD mice treated with the drug cocktail showed faster learning times, specifically in trial 2 for females (p<0.05) and trial 3 for males (p<0.05), compared to AD mice not receiving the drug cocktail. Following humane euthanasia, brain tissues will be assessed for Aβ and ptau neuropathology and pathways of aging using a combination of special stains and digital imaging to determine the cellular and molecular effects of the drug cocktail. The preliminary observation that the drug cocktail can prevent cognitive impairment associated with the early stages of AD suggests that targeting resilience to aging has potential translational implications for the early diagnosis and treatment of AD in human patients. Future efforts will work to establish molecular evidence of these observations and validate results in additional models of AD.

Aging is a complex indicator for the development of age-related diseases. Resilience to aging is defined as the ability to experience a stressor and return quickly to homeostasis. It is important to assess biological age quickly and accurately to fine-tune intervention strategies for non-resilient aging populations. The excision repair cross-complementation group 1 (ERCC1) is an endonuclease that plays a vital role in mediating the nucleotide excision repair of DNA, as well as being involved in the interstrand cross-link and double-strand break repair of DNA. Knockdowns of the gene significantly reduce the lifespan of the mouse due to an accumulation of damaged DNA. Previously it has been shown that wound healing is robustly correlated with DNA methylation clocks and age-related pathological features. In this study, we aim to understand whether a non-invasive wound healing assay is sensitive to accelerated aging phenotypes in an ERCC1 -/â–µ progeria model. In a preliminary study, mice 5 months old had a 2mm hole punched in each ear. The area was measured at 0 and 16 days time. The resulting healed area was compared against a standard curve where it was shown the accelerated aging mice were aged significantly older than the wild type (p<0.05). The lifespan of the mice also correlated with the wound healing (p<0.05). These findings indicate that a simple wound healing assay may be able to accurately assess biological age. Clinically, the ability to intervene and treat aging patients before they develop age-related pathology may help lengthen healthspan and postpone the onset of associated diseases. Future work will look to strengthen these findings with molecular evidence and pathological support.