# Biological Aging Contributions to Molecular Pathology and Neurodegeneration

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $736,014

## Abstract

Aging is among the most well-established risk factors for the accumulation of molecular pathology and
neurodegeneration with <1% of older adults lacking molecular pathology. As individuals age there is an
increased risk of neurofibrillary tau tangles (NFTs) co-occurring with amyloid-beta plaques (Aβ) consistent with
Alzheimer's disease (AD) neuropathological criteria. However, nearly all adults >50 years of age have
pathological evidence of NFTs which may occur in a similar spatial distribution to AD but typically less severe
in nature and in the absence of Aβ molecular pathology, consistent with a neuropathological diagnosis of
primary age-related tauopathy (PART). Therefore, it is currently unclear why most aging individuals develop
NFT pathology (i.e., either in PART or AD) and in variable degrees of severity while only a proportion of
individuals also develop Aβ pathology (i.e., in AD). To date the vast majority of aging research has defined
age-related pathological risk in chronological measurements (i.e., years since birth). However, the rates of
actual “biological” aspects of aging appear to differ between individuals, with some individuals displaying
features of aging that are accelerated (biological age older than their chronological age) or delayed (biological
age younger than their chronological age). The overarching goal of this proposal is to evaluate three sources of
biological aging mechanisms underlying risk and severity for NFT and Aβ molecular pathology and associated
neurodegeneration. First, DNA methylation (mDNA), or “the epigenetic clock”, can be measured to reliably
predict chronological age as well as accelerated or delayed aging. Second, telomeres are repetitive DNA
sequences and associated proteins that protect chromosome ends and shorten with cell division and age in
most human tissues, including brain. Third, we will evaluate single nucleotide polymorphisms (SNPs)
associated with reduced longevity and shortened telomere length to help identify risk factors of poor biological
aging to facilitate early interventions and pinpoint candidate genetic mechanisms for novel therapeutic
approaches. Together, we propose to use mDNA and shortest telomere length analysis (TeSLA) along with
complementary SNP association tests to evaluate the hypothesis that accelerated aging (biological age older
than chronological age) will increase the risk of molecular pathology and neurodegeneration. We will assess
biological aging in well-characterized PART and AD autopsy-confirmed samples and in vivo structural MRI and
PET molecular markers of 18F-floretaucipir (tau) and 18F-florbetaben (Aβ) in aging controls from our NIA-funded
Alzheimer's Disease Center (ADC) and collaborating ADCs. By investigating the biological aging mechanisms
of NFT and Aβ pathology, this proposal addresses a NIH priority to improve our “Understanding of Alzheimer's
Disease in the Context of the Aging Brain”. A significant proportion of the aging population has varying ...

## Key facts

- **NIH application ID:** 10414065
- **Project number:** 5R01AG066152-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Corey T McMillan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $736,014
- **Award type:** 5
- **Project period:** 2019-09-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10414065

## Citation

> US National Institutes of Health, RePORTER application 10414065, Biological Aging Contributions to Molecular Pathology and Neurodegeneration (5R01AG066152-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10414065. Licensed CC0.

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