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Investigating the interplay between hallmarks of aging; protein glycation, nutrient sensing, and senescence

Award Number: R56AG082819
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Investigating the interplay between hallmarks of aging; protein glycation, nutrient sensing, and senescence - PROJECT SUMMARY Cellular senescence and deregulated nutrient sensing (insulin signaling and/or insulin resistance), two hallmarks of aging, are implicated in the loss of physiological function and etiology of age-related diseases. Advanced glycation end products (AGEs) are a source of increased protein glycation burden, a manifestation of another hallmark of aging, loss of proteostasis. Methylglyoxal (MGO), a reactive precursor to AGEs, influences the pathophysiology of insulin resistance (IR) and cellular senescence. A recent study indicates that IR accelerates β-cell senescence leading to functional decline in pancreatic tissue and worsening metabolic profile. Emerging evidence also suggests that the accumulation of senescent cells in adipose tissue directly regulates the IR phenotypes. Current investigations established the co-occurrence of these two aging hallmarks. However, a major gap in our knowledge exists in understanding the interactions between both the hallmarks and the impact of normal and pathological aging on these interactions. Our long-term goal is to further investigate this emerging and exciting area of research in the context of tissue-specific communication that dictates interactions among aging hallmarks. The present proposal will specifically ask the following critical questions: (a) how do these three hallmarks of aging interact with each other; (b) is there any tissue-specific hierarchy and interdependency between the three hallmarks in different tissues; (c) can multiple interventions which overcome these hallmarks of aging show additive protection to slow aging and age-related diseases. Our central hypothesis is that MGO- induced protein glycation not only acts as an endogenous driver for IR and cellular senescence but also plays a key role in the interplay between these two hallmarks in the adipose tissue and pancreas. We will test the hypothesis by pursuing the following Specific Aims: 1) the role of methylglyoxal in inducing senescence in the pancreatic β-cells and adipose tissue through protein glycation; 2) the role of methylglyoxal in inducing IR in adipose tissue or insulin release from pancreatic β-cells through protein glycation; and 3) investigate the interplay between MGO-induced protein glycation IR and cellular senescence. Preadipocytes and primary β-cells will be used to study the role of MGO in inducing tissue-specific senescence and IR. We will also utilize senolytics to determine the importance of senescent cells in MGO-induced IR. We will also determine the therapeutic potential of combing a novel glycation-lowering cocktail, Gly-Low, with or without a senolytic for their impact on ameliorating IR, senescence, and lifespan in a physiological (high-fat diet) model. A key significance of this work is helping us understand the interconnectivity among MGO-induced protein glycation burden, IR, and cellular senescence, thereby shedding light on how these hallmarks interact with each other under stress conditions and how this knowledge can be used to slow aging and ameliorate age-related diseases.


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: 2026 ( Subtotal = $0 )
2026	2023	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	1	1/29/2026	NEW	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	1	3/13/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $444,220 )
2023	2023	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	1	9/22/2023	NEW	$444,220
														Subtotal = $444,220

Grand Total All Awards = $444,220

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Investigating the interplay between hallmarks of aging; protein glycation, nutrient sensing, and senescence

Award Number: R56AG082819

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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