Wednesday, September 17, 2025 9/17/2025

Molecular mechanisms of aging and accelerated aging in the human brain

Award Number: R01AG079799
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Molecular mechanisms of aging and accelerated aging in the human brain - SUMMARY. This proposal is in response to PAR-21-038: Stephen I. Katz Early Stage Investigator Research Project Grant. Aging is a major risk factor for the development of cognitive deficits and neurodegenerative diseases. Understanding the exact molecular mechanisms of brain aging and accelerated brain aging can lead to the development of novel interventions to delay or potentially reverse brain aging. Environmental factors including viral infections (such as SARS-CoV-2, the virus that caused the COVID-19 pandemic) have been shown to be associated with cognitive decline and accelerated brain aging. However, the exact molecular mechanisms underlying the effects of environmental factors, and specifically COVID-19, on brain aging remain unknown. Our long-term goal is to identify key factors that induce accelerated brain aging, so that therapeutics can be developed to delay or reverse brain aging. The overall objective of this proposal is to identify genes and regulators of gene expression that cause brain aging and accelerated brain aging in COVID-19 patients. Previous research from our group showed that many microRNAs (miRNAs), which are small non-coding RNAs that induce an orchestrated regulation of gene expression, are differentially expressed in the aged mouse brain and regulate aging. Based on those data and our recently published bulk RNA sequencing studies showing molecular signatures of brain aging in COVID-19 patients, our central hypothesis is that dysregulated gene and miRNA expression is an important facet of accelerated brain aging. Previous studies using microarray and bulk RNA sequencing approaches showed that aging induces distinct molecular signatures in the human frontal cortex. While layer enriched expression signatures have been identified in the human frontal cortex, the spatial topography of molecular signatures of aging remain largely unknown. Here, we will utilize state-of-the-art spatial transcriptomic technologies to analyze human frontal cortex sections from healthy individuals across lifespan, as well as frontal cortex sections from COVID-19 patients (and appropriate controls) to identify spatially distinct aging-regulated transcriptomic changes. We will investigate the effects of aging-regulated genes on cellular senescence using in vitro assays. To better understand regulatory mechanisms of aging-regulated gene expression, we will measure the expression of miRNAs in healthy individuals across lifespan and COVID-19 cases on similar frontal cortex sections and we will identify aging-regulated mRNA targets for candidate miRNAs. Finally, we will test the potential of miRNAs to accelerate and delay aging using in vitro assays and in vivo mouse models. These studies are expected to have a significant impact as they will determine novel targets for the development of therapeutics to delay or reverse brain aging and aging-related neuropathology. This proposal is highly relevant to public health and to the NIA’s mission of advancing knowledge on the causes of aging processes and age-associated diseases to extend healthy lifespan.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $828,774 )
2025	2025	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Aging Research	000	3	8/22/2025	NON-COMPETING CONTINUATION	$828,774
														Subtotal = $828,774

Issue Date FY: 2024 ( Subtotal = $855,196 )
2024	2024	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Aging Research	000	2	6/3/2024	NON-COMPETING CONTINUATION	$855,196
														Subtotal = $855,196

Issue Date FY: 2023 ( Subtotal = $841,971 )
2023	2023	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Aging Research	000	1	9/13/2023	NEW	$841,971
														Subtotal = $841,971

Grand Total All Awards = $2,525,941

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Molecular mechanisms of aging and accelerated aging in the human brain

Award Number: R01AG079799

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/15/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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