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Principal Investigator: ALEXANDER A SOUKAS
Organization: MASSACHUSETTS GENERAL HOSPITAL
Fiscal Year: 2024
Award: $420,000
Funding agency: National Institute on Aging
A growing body of evidence suggests that metformin effects on mitochondria are responsible for its ability to
lower blood glucose and reduce the growth and incidence of cancer. In model systems, metformin prolongs
lifespan, and observational studies in humans similarly suggest a longevity benefit for patients who take
metformin. In spite of recent progress in the biology of metformin action, the mechanisms by which metformin
exacts favorable effects on longevity and aging remain incompletely characterized. Our recent work provides
evidence that metformin targets multiple, fundamental aspects of the aging process. In particular, we have
shown that metformin-mediated inhibition of mitochondrial energetics restrains transport through the nuclear
pore complex (NPC). Restrained NPC transport locks the pro-aging kinase mTORC1 in the inactive state. It is
known that many cells obtain a “leaky” nucleus as they age, and our work is the first suggestion that metformin
can target this leakiness through action on mitochondria. Our preliminary data and published studies indicate
that metformin can also target mitochondrial leakiness that is mechanistically linked to aging. These exciting
observations suggest that metformin is positioned to reverse multiple, pathological cellular changes that occur
with aging. In doing so, the drug is poised to fulfill the geroscience principle: by reversing fundamental aspects
of the aging process, metformin may target not one but many aging-associated diseases simultaneously. In
spite of this tantalizing possibility, critical gaps in our knowledge remain that prevent us from fully realizing the
therapeutic potential of metformin. In which tissues is metformin action needed to promote longevity? How are
metformin effects at mitochondria transduced to effectors that mediate the drug’s geroprotective effects? What
is the full spectrum of molecular events required for metformin effects in aging? The overall objective of this
application is to determine the sites and mechanisms of metformin action in aging. The central hypothesis of
this proposal is that metformin promotes healthy aging by targeting mitochondrial energetics in specific tissues,
which signals through downstream effector pathways to promote longevity. The rationale for this work is that
completion of the project will illuminate both specific effector sites of the drug and unexpected elements of the
metformin response pathway. In Aim 1 we will define mechanisms by which metformin targets mitochondria to
promote longevity. Aim 2 will characterize mechanisms by which metformin reduces mitochondrial permeability
in aging. In Aim 3, we will probe a larger landscape of metformin response genes in order to understand the full
spectrum of metformin’s direct and indirect cellular effects in aging. This project is significant because it will
elucidate the molecular mechanisms by which biguanides mediate their positive effects on lifespan. We put
forth conceptual and technical innovations that will allow discovery of the most important aspects of the
response to metformin. Successful completion of this project will pave the way for a new generation of
strategies that can promote healthy aging and reduce the onset and severity of aging-related diseases.
Terms: <5'-Adenylic acid><ATP-protein phosphotransferase><Adenosine Monophosphate><Adenylic Acid><Age><Aging><Biguanides><Biologic Models><Biological Models><Biology><Blood Glucose><Blood Sugar><Body Tissues><C elegans><C. elegans><C.elegans><Caenorhabditis elegans><Cancers><Cell Body><Cell Communication and Signaling><Cell Nucleus><Cell Signaling><Cells><Complex><Data><Diabetes Mellitus><Dimethylbiguanidine><Dimethylguanylguanidine><Drugs><Elements><Event><FK506 Binding Protein 12-Rapamycin Associated Protein 1><FKBP12 Rapamycin Complex Associated Protein 1><FRAP1><FRAP1 gene><FRAP2><Gene Expression><Generalized Growth><Generations><Genes><Genetic><Genomics><Geroscience><Goals><Growth><Health><Health Benefit><Health Promotion><Human><Hypoglycemic Agents><Hypoglycemic Drugs><Hypoglycemics><Incidence><Increase lifespan><Intracellular Communication and Signaling><Kinase Family Gene><Kinases><Knowledge><Laboratories><Length of Life><Link><Longevity><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Mechanistic Target of Rapamycin><Mediating><Medication><Metformin><Mice><Mice Mammals><Mitochondria><Model System><Modern Man><Molecular><Morbidity><Morbidity - disease rate><Murine><Mus><N,N-dimethyl-imidodicarbonimidic diamide><NPC><Nuclear Pore Complex><Nucleus><Observation research><Observation study><Observational Study><Observational research><Oral><Pathologic><Pathway interactions><Patients><Permeability><Pharmaceutical Preparations><Phosphotransferase Gene><Phosphotransferases><Position><Positioning Attribute><Protein Kinase><Proteomics><Publishing><RAFT1><Response Elements><Salutogenesis><Severities><Signal Transduction><Signal Transduction Systems><Signaling><Site><Suggestion><Therapeutic><Tissue Growth><Tissues><Translating><Transphosphorylases><Work><ages><aging associated disease><aging process><aging related disease><antihyperglycemic><biological signal transduction><cancer cell><cellular targeting><combat><diabetes><disease of aging><disorder of aging><drug/agent><elongating the lifespan><extend life span><extend lifespan><functional genomics><gene function><genetic approach><genetic strategy><genome editing><genome wide screen><genomic editing><geroprotective><geroprotector><geroscientific><glycogen synthase a kinase><health-span><healthspan><healthy aging><healthy human aging><healthy life span><human data><hydroxyalkyl protein kinase><innovate><innovation><innovative><interest><life span><lifespan><lifespan extension><mTOR><mTOR inhibition><malignancy><mammalian target of rapamycin><member><mitochondrial><model organism><molecular imaging><molecule imaging><mortality><neoplasm/cancer><ontogeny><pathway><phosphorylase b kinase kinase><prevent><preventing><pro-aging><progeronic><promote aging><promoting health><prospective><response><restraint><therapeutic target>