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Mitochondrial mechanisms of maternal age effects on offspring health and lifespan

Award Number: R01AG076592
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Mitochondrial mechanisms of maternal age effects on offspring health and lifespan - 7. PROJECT SUMMARY Advanced maternal age at the time of reproduction decreases offspring lifespan and health in a range of species, including humans. The mechanisms controlling maternal age effects on offspring are unknown, however. Mitochondria are prone to damage and dysfunction with age and are maternally inherited, suggesting they may play a role in intergenerational maternal effects on offspring health. Our work shows that offspring from older mothers have shorter lifespan, lower reproduction, decreased health, and altered behavior relative to young- mother offspring. We found that these changes are associated with higher mtDNA per cell, more mitochondria, larger mitochondria, decreased mitochondrial intermembrane area, lower oxidative potential, lower ATP content, and altered reactive oxygen species (ROS) levels. Our results and the literature on mitochondria in aging led to our hypothesis that mitochondrial dysfunction in advanced maternal age causes accumulation of dysfunctional mitochondria in offspring through compensatory biogenesis and decreased autophagy during development. This disrupts offspring mitochondrial function and mitochondrial-nuclear communication, leading to accelerated offspring aging. The objective of this project is to understand the mitochondrial mechanisms by which maternal age determines offspring aging. In this study, we will: (1) identify the maternal mitochondrial mechanisms that trigger maternal age effects; (2) identify the developmental mechanisms causing accumulation of mtDNA and damaged mitochondria in old-mother offspring; and (3) identify the offspring mitochondrial mechanisms involved in negative maternal age effects and determine if these mechanisms are ROS-dependent. This work will be accomplished using qPCR and RNA-Seq to quantify mtDNA and controls on metabolism, signaling, and dynamics; imaging to quantify mitochondrial ultrastructure and mitophagy, and pharmacological and RNAi manipulation of maternal and offspring mitochondria to test mechanisms. We will use biochemical, respirometry, and imaging approaches to measure mitochondrial efficiency. Additional biochemical and imaging approaches will be used to quantify ROS and cellular damage. We will use lifetable experiments to measure lifespan and reproduction in response to maternal age or mechanistic tests. Studies will be on both female and male offspring. Our study system is the rotifer Brachionus manjavacas—a short-lived, aquatic, microscopic invertebrate with unique advantages as a model for investigating maternal age effects. Our approach will identify the cellular mechanisms by which advanced maternal age causes accumulation of mtDNA and damaged mitochondria in offspring; changes offspring mitochondrial dynamics, structure, and function; and decreases offspring fitness. If successful, this research will advance the field by revealing drivers of accelerated aging in offspring due to maternal age effects and by identifying mechanisms underlying a poorly understood cause of interindividual variability in healthspan and lifespan. Our findings will have implications for understanding age-related changes in female fertility and for identifying potential targets for treatment of age-related dysfunction.


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 = $347,475 )
2026	2026	THE MARINE BIOLOGICAL LABORATORY	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Aging Research	000	5	1/30/2026	NON-COMPETING CONTINUATION	$312,728
2026	2026	THE MARINE BIOLOGICAL LABORATORY	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Aging Research	001	5	2/25/2026	NON-COMPETING CONTINUATION	$34,747
														Subtotal = $347,475

Issue Date FY: 2025 ( Subtotal = $340,526 )
2025	2025	THE MARINE BIOLOGICAL LABORATORY	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Aging Research	000	4	3/13/2025	NON-COMPETING CONTINUATION	$312,728
2025	2025	THE MARINE BIOLOGICAL LABORATORY	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Aging Research	001	4	6/18/2025	NON-COMPETING CONTINUATION	$27,798
														Subtotal = $340,526

Issue Date FY: 2024 ( Subtotal = $347,475 )
2024	2024	THE MARINE BIOLOGICAL LABORATORY	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Aging Research	000	3	3/12/2024	NON-COMPETING CONTINUATION	$312,728
2024	2024	THE MARINE BIOLOGICAL LABORATORY	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Aging Research	001	3	6/28/2024	NON-COMPETING CONTINUATION	$34,747
														Subtotal = $347,475

Issue Date FY: 2023 ( Subtotal = $469,515 )
2023	2023	THE MARINE BIOLOGICAL LABORATORY	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Aging Research	001	2	8/25/2023	SUPPLEMENT FOR EXPANSION	$122,040
2023	2023	THE MARINE BIOLOGICAL LABORATORY	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Aging Research	000	2	3/6/2023	NON-COMPETING CONTINUATION	$347,475
														Subtotal = $469,515

Issue Date FY: 2022 ( Subtotal = $347,475 )
2022	2022	MARINE BIOLOGICAL LABORATORY, THE	7 M B L ST	WOODS HOLE	MA	02543	BARNSTABLE	USA	Aging Research	000	1	6/9/2022	NEW	$347,475
														Subtotal = $347,475

Grand Total All Awards = $1,852,466

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Mitochondrial mechanisms of maternal age effects on offspring health and lifespan

Award Number: R01AG076592

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/15/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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