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  1. Article: Quantification of healthspan in aging mice: Introducing FAMY and GRAIL.

    Lamming, Dudley W

    bioRxiv : the preprint server for biology

    2024  

    Abstract: The population around the world is graying, and as many of these individuals will spend years suffering from the burdens of age associated diseases, understanding how to increase healthspan, defined as the period of life free from disease and disability, ...

    Abstract The population around the world is graying, and as many of these individuals will spend years suffering from the burdens of age associated diseases, understanding how to increase healthspan, defined as the period of life free from disease and disability, is an urgent priority of geroscience research. The lack of agreed-upon quantitative metrics for measuring healthspan in aging mice has slowed progress in identifying interventions that do not simply increase lifespan, but also healthspan. Here, we define FAMY (Frailty-Adjusted Mouse Years) and GRAIL (Gauging Robust Aging when Increasing Lifespan) as new summary statistics for quantifying healthspan in mice. FAMY integrates lifespan data with longitudinal measurements of a widely utilized clinical frailty index, while GRAIL incorporates these measures and also adds information from widely utilized healthspan assays and the hallmarks of aging. Both metrics are conceptually similar to quality-adjusted life years (QALY), a widely-utilized measure of disease burden in humans, and can be readily calculated from data acquired during longitudinal and cross-sectional studies of mouse aging. We find that interventions generally thought to promote health, including calorie restriction, robustly improve healthspan as measured by FAMY and GRAIL. Finally, we show that the use of GRAIL provides new insights, and identify dietary restriction of protein or isoleucine as interventions that robustly promote healthspan but not longevity in female HET3 mice. We suggest that the routine integration of these measures into studies of aging in mice will allow the identification and development of interventions that promote healthy aging even in the absence of increased lifespan.
    Language English
    Publishing date 2024-03-17
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.11.07.566044
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  2. Article ; Online: Quantification of healthspan in aging mice: introducing FAMY and GRAIL.

    Lamming, Dudley W

    GeroScience

    2024  

    Abstract: The population around the world is graying, and as many of these individuals will spend years suffering from the burdens of age associated diseases, understanding how to increase healthspan, defined as the period of life free from disease and disability, ...

    Abstract The population around the world is graying, and as many of these individuals will spend years suffering from the burdens of age associated diseases, understanding how to increase healthspan, defined as the period of life free from disease and disability, is an urgent priority of geroscience research. The lack of agreed-upon quantitative metrics for measuring healthspan in aging mice has slowed progress in identifying interventions that do not simply increase lifespan, but also healthspan. Here, we define FAMY (Frailty-Adjusted Mouse Years) and GRAIL (Gauging Robust Aging when Increasing Lifespan) as new summary statistics for quantifying healthspan in mice. FAMY integrates lifespan data with longitudinal measurements of a widely utilized clinical frailty index, while GRAIL incorporates these measures and also adds information from widely utilized healthspan assays and the hallmarks of aging. Both metrics are conceptually similar to quality-adjusted life years (QALY), a widely utilized measure of disease burden in humans, and can be readily calculated from data acquired during longitudinal and cross-sectional studies of mouse aging. We find that interventions generally thought to promote health, including calorie restriction, robustly improve healthspan as measured by FAMY and GRAIL. Finally, we show that the use of GRAIL provides new insights, and identify dietary restriction of protein or isoleucine as interventions that robustly promote healthspan but not longevity in female HET3 mice. We suggest that the routine integration of these measures into studies of aging in mice will allow the identification and development of interventions that promote healthy aging even in the absence of increased lifespan.
    Language English
    Publishing date 2024-05-17
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2886586-8
    ISSN 2509-2723 ; 2509-2715
    ISSN (online) 2509-2723
    ISSN 2509-2715
    DOI 10.1007/s11357-024-01200-5
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  3. Article ; Online: Targeting the biology of aging with mTOR inhibitors.

    Mannick, Joan B / Lamming, Dudley W

    Nature aging

    2023  Volume 3, Issue 6, Page(s) 642–660

    Abstract: Inhibition of the protein kinase mechanistic target of rapamycin (mTOR) with the Food and Drug Administration (FDA)-approved therapeutic rapamycin promotes health and longevity in diverse model organisms. More recently, specific inhibition of mTORC1 to ... ...

    Abstract Inhibition of the protein kinase mechanistic target of rapamycin (mTOR) with the Food and Drug Administration (FDA)-approved therapeutic rapamycin promotes health and longevity in diverse model organisms. More recently, specific inhibition of mTORC1 to treat aging-related conditions has become the goal of basic and translational scientists, clinicians and biotechnology companies. Here, we review the effects of rapamycin on the longevity and survival of both wild-type mice and mouse models of human diseases. We discuss recent clinical trials that have explored whether existing mTOR inhibitors can safely prevent, delay or treat multiple diseases of aging. Finally, we discuss how new molecules may provide routes to the safer and more selective inhibition of mTOR complex 1 (mTORC1) in the decade ahead. We conclude by discussing what work remains to be done and the questions that will need to be addressed to make mTOR inhibitors part of the standard of care for diseases of aging.
    MeSH term(s) Animals ; Humans ; Mice ; Aging ; Biology ; Mechanistic Target of Rapamycin Complex 1 ; MTOR Inhibitors ; Sirolimus ; TOR Serine-Threonine Kinases ; United States
    Chemical Substances Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; MTOR Inhibitors ; Sirolimus (W36ZG6FT64) ; TOR Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2023-05-04
    Publishing country United States
    Document type Journal Article ; Review
    ISSN 2662-8465
    ISSN (online) 2662-8465
    DOI 10.1038/s43587-023-00416-y
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  4. Article ; Online: Blazing a trail for the clinical use of rapamycin as a geroprotecTOR.

    Konopka, Adam R / Lamming, Dudley W

    GeroScience

    2023  Volume 45, Issue 5, Page(s) 2769–2783

    Abstract: Treatment with rapamycin, an inhibitor of the mechanistic Target Of Rapamycin Complex One (mTORC1) protein kinase, has been repeatedly demonstrated to extend lifespan and prevent or delay age-related diseases in diverse model systems. Concerns over the ... ...

    Abstract Treatment with rapamycin, an inhibitor of the mechanistic Target Of Rapamycin Complex One (mTORC1) protein kinase, has been repeatedly demonstrated to extend lifespan and prevent or delay age-related diseases in diverse model systems. Concerns over the risk of potentially serious side effects in humans, including immunosuppression and metabolic disruptions, have cautiously limited the translation of rapamycin and its analogs as a treatment for aging associated conditions. During the last decade, we and others have developed a working model that suggests that while inhibition of mTORC1 promotes healthy aging, many of the negative side effects of rapamycin are associated with "off-target" inhibition of a second mTOR complex, mTORC2. Differences in the kinetics and molecular mechanisms by which rapamycin inhibits mTORC1 and mTORC2 suggest that a therapeutic window for rapamycin could be exploited using intermittent dosing schedules or alternative rapalogs that may enable more selective inhibition of mTORC1. However, the optimal dosing schedules and the long-term efficacy of such interventions in humans are unknown. Here, we highlight ongoing or upcoming clinical trials that will address outstanding questions regarding the safety, pharmacokinetics, pharmacodynamics, and efficacy of rapamycin and rapalogs on several clinically oriented outcomes. Results from these early phase studies will help guide the design of phase 3 clinical trials to determine whether rapamycin can be used safely to inhibit mTORC1 for the treatment and prevention of age-related diseases in humans.
    MeSH term(s) Humans ; Sirolimus/pharmacology ; Senotherapeutics ; Mechanistic Target of Rapamycin Complex 1 ; MTOR Inhibitors ; Mechanistic Target of Rapamycin Complex 2
    Chemical Substances Sirolimus (W36ZG6FT64) ; Senotherapeutics ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; MTOR Inhibitors ; Mechanistic Target of Rapamycin Complex 2 (EC 2.7.11.1)
    Language English
    Publishing date 2023-10-06
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2886586-8
    ISSN 2509-2723 ; 2509-2715
    ISSN (online) 2509-2723
    ISSN 2509-2715
    DOI 10.1007/s11357-023-00935-x
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  5. Article ; Online: Geroprotective interventions in the 3xTg mouse model of Alzheimer's disease.

    Sonsalla, Michelle M / Lamming, Dudley W

    GeroScience

    2023  Volume 45, Issue 3, Page(s) 1343–1381

    Abstract: Alzheimer's disease (AD) is an age-associated neurodegenerative disease. As the population ages, the increasing prevalence of AD threatens massive healthcare costs in the coming decades. Unfortunately, traditional drug development efforts for AD have ... ...

    Abstract Alzheimer's disease (AD) is an age-associated neurodegenerative disease. As the population ages, the increasing prevalence of AD threatens massive healthcare costs in the coming decades. Unfortunately, traditional drug development efforts for AD have proven largely unsuccessful. A geroscience approach to AD suggests that since aging is the main driver of AD, targeting aging itself may be an effective way to prevent or treat AD. Here, we discuss the effectiveness of geroprotective interventions on AD pathology and cognition in the widely utilized triple-transgenic mouse model of AD (3xTg-AD) which develops both β-amyloid and tau pathologies characteristic of human AD, as well as cognitive deficits. We discuss the beneficial impacts of calorie restriction (CR), the gold standard for geroprotective interventions, and the effects of other dietary interventions including protein restriction. We also discuss the promising preclinical results of geroprotective pharmaceuticals, including rapamycin and medications for type 2 diabetes. Though these interventions and treatments have beneficial effects in the 3xTg-AD model, there is no guarantee that they will be as effective in humans, and we discuss the need to examine these interventions in additional animal models as well as the urgent need to test if some of these approaches can be translated from the lab to the bedside for the treatment of humans with AD.
    MeSH term(s) Mice ; Humans ; Animals ; Alzheimer Disease/prevention & control ; Alzheimer Disease/drug therapy ; Amyloid beta-Protein Precursor/metabolism ; Amyloid beta-Protein Precursor/therapeutic use ; tau Proteins/metabolism ; Neurodegenerative Diseases ; Diabetes Mellitus, Type 2 ; Mice, Transgenic ; Disease Models, Animal
    Chemical Substances Amyloid beta-Protein Precursor ; tau Proteins
    Language English
    Publishing date 2023-04-06
    Publishing country Switzerland
    Document type Journal Article ; Review ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2886586-8
    ISSN 2509-2723 ; 2509-2715
    ISSN (online) 2509-2723
    ISSN 2509-2715
    DOI 10.1007/s11357-023-00782-w
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  6. Article ; Online: The central moTOR of metabolism.

    Simcox, Judith / Lamming, Dudley W

    Developmental cell

    2022  Volume 57, Issue 6, Page(s) 691–706

    Abstract: The protein kinase mechanistic target of rapamycin (mTOR) functions as a central regulator of metabolism, integrating diverse nutritional and hormonal cues to control anabolic processes, organismal physiology, and even aging. This review discusses the ... ...

    Abstract The protein kinase mechanistic target of rapamycin (mTOR) functions as a central regulator of metabolism, integrating diverse nutritional and hormonal cues to control anabolic processes, organismal physiology, and even aging. This review discusses the current state of knowledge regarding the regulation of mTOR signaling and the metabolic regulation of the four macromolecular building blocks of the cell: carbohydrate, nucleic acid, lipid, and protein by mTOR. We review the role of mTOR in the control of organismal physiology and aging through its action in key tissues and discuss the potential for clinical translation of mTOR inhibition for the treatment and prevention of diseases of aging.
    MeSH term(s) Mechanistic Target of Rapamycin Complex 1/metabolism ; Signal Transduction/physiology ; Sirolimus/pharmacology ; TOR Serine-Threonine Kinases/metabolism
    Chemical Substances Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; TOR Serine-Threonine Kinases (EC 2.7.11.1) ; Sirolimus (W36ZG6FT64)
    Language English
    Publishing date 2022-03-21
    Publishing country United States
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2054967-2
    ISSN 1878-1551 ; 1534-5807
    ISSN (online) 1878-1551
    ISSN 1534-5807
    DOI 10.1016/j.devcel.2022.02.024
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  7. Article ; Online: Strength in diversity: Intra-cellular metabolite sharing enhances longevity.

    Lamming, Dudley W / Anderson, Rozalyn M

    Cell

    2022  Volume 186, Issue 1, Page(s) 8–9

    Abstract: Much of our foundational knowledge of cellular biology comes from studies in budding yeast, often described as a simple unicellular eukaryotic model. In this issue of Cell, Correia-Melo et al. describe an unappreciated feature of yeast biology involving ... ...

    Abstract Much of our foundational knowledge of cellular biology comes from studies in budding yeast, often described as a simple unicellular eukaryotic model. In this issue of Cell, Correia-Melo et al. describe an unappreciated feature of yeast biology involving intra-cellular metabolite exchange, where cells adapt and respond as part of a community, and go on to show that sharing of resources linked to methionine metabolism enhances longevity of cooperating cells.
    MeSH term(s) Longevity ; Saccharomyces cerevisiae/metabolism ; Eukaryotic Cells ; Cytoplasm ; Saccharomycetales
    Language English
    Publishing date 2022-12-28
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Comment
    ZDB-ID 187009-9
    ISSN 1097-4172 ; 0092-8674
    ISSN (online) 1097-4172
    ISSN 0092-8674
    DOI 10.1016/j.cell.2022.12.012
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  8. Article ; Online: The regulation of healthspan and lifespan by dietary amino acids.

    Babygirija, Reji / Lamming, Dudley W

    Translational medicine of aging

    2021  Volume 5, Page(s) 17–30

    Abstract: As a key macronutrient and source of essential macromolecules, dietary protein plays a significant role in health. For many years, protein-rich diets have been recommended as healthy due to the satiety-inducing and muscle-building effects of protein, as ... ...

    Abstract As a key macronutrient and source of essential macromolecules, dietary protein plays a significant role in health. For many years, protein-rich diets have been recommended as healthy due to the satiety-inducing and muscle-building effects of protein, as well as the ability of protein calories to displace allegedly unhealthy calories from fats and carbohydrates. However, clinical studies find that consumption of dietary protein is associated with an increased risk of multiple diseases, especially diabetes, while studies in rodents have demonstrated that protein restriction can promote metabolic health and even lifespan. Emerging evidence suggests that the effects of dietary protein on health and longevity are not mediated simply by protein quantity but are instead mediated by protein quality - the specific amino acid composition of the diet. Here, we discuss how dietary protein and specific amino acids including methionine, the branched chain amino acids (leucine, isoleucine, and valine), tryptophan and glycine regulate metabolic health, healthspan, and aging, with attention to the specific molecular mechanisms that may participate in these effects. Finally, we discuss the potential applicability of these findings to promoting healthy aging in humans.
    Language English
    Publishing date 2021-05-24
    Publishing country Netherlands
    Document type Journal Article
    ISSN 2468-5011
    ISSN (online) 2468-5011
    DOI 10.1016/j.tma.2021.05.001
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  9. Article ; Online: We are more than what we eat.

    Green, Cara L / Lamming, Dudley W

    Nature metabolism

    2021  Volume 3, Issue 9, Page(s) 1144–1145

    Language English
    Publishing date 2021-08-25
    Publishing country Germany
    Document type Journal Article
    ISSN 2522-5812
    ISSN (online) 2522-5812
    DOI 10.1038/s42255-021-00434-3
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  10. Article ; Online: A food with medicine approach to health.

    Green, Cara L / Lamming, Dudley W

    Cell metabolism

    2021  Volume 33, Issue 12, Page(s) 2303–2304

    Abstract: There is significant interest in identifying compounds that mimic the effects of dietary restriction on healthy aging. In the latest issue of Cell Metabolism, Le Couteur et al. (2021) use a nutritional geometry approach to survey the effects of three ... ...

    Abstract There is significant interest in identifying compounds that mimic the effects of dietary restriction on healthy aging. In the latest issue of Cell Metabolism, Le Couteur et al. (2021) use a nutritional geometry approach to survey the effects of three such compounds on the hepatic proteome across a changing dietary landscape.
    MeSH term(s) Diet ; Food
    Language English
    Publishing date 2021-10-23
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Comment
    ZDB-ID 2176834-1
    ISSN 1932-7420 ; 1550-4131
    ISSN (online) 1932-7420
    ISSN 1550-4131
    DOI 10.1016/j.cmet.2021.11.012
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