Advancing Healthy Aging and Longevity Through Geroscience Research

Utilizing the geroscience paradigm, researchers explore targeting aging processes to extend healthspan and lifespan. The TAME Aging Outcomes Trial aims to test this hypothesis with metformin, a drug that shows promise in impacting aging-related pathways. By focusing on delaying the onset of multiple age-related diseases, the trial could revolutionize approaches to combating aging and improving overall well-being in aging populations.

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• Geroscience
• Aging research
• TAME trial
• Metformin
• Longevity

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Uploaded on Jul 01, 2024 | 0 Views

Presentation Transcript

1. Update on the Targeting Aging with MEtformin: the TAME Aging Outcomes Trial Stephen B. Kritchevsky, PhD

2. Alternative Strategies for an Aging Society Delay a specific disease through controlling specific risk factors Good for the one disease Current FDA Way of Thinking Delay aging Delay multiple age-related diseases (by targeting basic molecular processes of aging) The New Geroscience Paradigm

3. 3 Premises from Geroscience: 1) aging is the major common risk factor for many diseases that accumulate rapidly in older adults 2) aging has a distinct and increasingly well described biology 3) this biology can be targeted, which has been shown to extend the healthspan and lifespan of preclinical models and may be feasible in humans Wake Forest Baptist Medical Center

4. Clinical trial to test the geroscience hypothesis provide immediate clinical application with potential to extend healthy lifespan and reduce healthcare costs serve as a template for future efforts and drug development increase scientific knowledge and facilitate discovery of biomarkers establish standard of proof against which the anti-aging claims of nutraceutical or pharmaceutical companies could be judged Wake Forest Baptist Medical Center

5. Metformin as a drug that targets aging Pleiotropic Effects Inflammation Cellular Senescence (?) Epigenetics Mitochondrial Dysfunction Proteostasis & Autophagy Deregulated Nutrient Sensing for detail & examples see Barzilai et al. Cell Metabolism, 2016.

6. Multiple Morbidity Composite Outcome If a drug s effect is on aging it should reduce the incidence of multiple diseases including those that share few risk factors other than age. The outcome of interest is the time to incidence of one of a collection of possible disease endpoints. This collection is a composite endpoint of multiple age- related morbidities. 6 Wake Forest Baptist Medical Center

7. Selecting Diseases for the Composite Age is the most important risk factor. Evidence that aging biology targeted by the treatment plays a role in its occurrence. Not a biochemical diagnosis [per FDA]. Existing data supporting an effect of the proposed intervention. 7 Wake Forest Baptist Medical Center

8. Geroscience Hypothesis: target biological aging processes to delay incidence of chronic diseases or disability 7/1/2024 Adapted from Justice et al.CEM, 2018. Wake Forest Baptist Medical Center 8

9. TAME Aging Outcomes Trial Age 65-80 years AND Slow gait speed OR Age-related disease Inclusion Criteria n = 3000, 6-year, 14 Clinical Sites; double-blind randomized placebo controlled trial Metformin (1500 mg 1 day) vs. Placebo (0 mg 1 day) (Clinical) Time to incidence of any age-related disease: MI, stroke, CHF, cancer*, MCI/dementia, or death. Primary Outcome Secondary Outcome (Functional) Decline in mobility or cognitive function. American Federation for Aging Research Funded Aging Outcomes Trial Proposed Biorepository & Biomarkers Resource & Biomarkers Outcomes (Biological)Change in biomarkers of aging. * Excluding non-melanoma skin cancer and prostate cancer

10. Metformin and age-related diseases Preliminary data from trials & observational studies Disease Prevention of type 2 diabetes Strength of association ++++ Prevention of CVD Prevention of cancer Prevention of dementia Reduction in mortality +++ ++ (observational) ++ (observational) ++ 10 Wake Forest Baptist Medical Center

11. Observational studies of metformin and CVD outcomes Observational studies Roumie (2012) Population Comparator Outcome Effect size VA/Medicare database Canadian prescription drug database SU MACE 21% (HR 1.21) Johnson (2005) SU CVD hospitalization or death MACE 19% (HR 0.81) Schramm (2011) Danish SU 19-32% (HR 1.19-1.32) population database REACH Registry (DM w/CVD or multiple risk factors) Medicare database: DM hospitalized for CHF VA patients with CHF Roussel (2010) Non-use mortality 24% RRR (HR 0.76) Masoudi (2005) Other DM meds (not sensitizers) Mortality Readmission for CHF 13% RR (HR .87) 8% (HR 0.92) Aguilar (2011) Non-use Mortality 24% RR (HR 0.76) 11 Wake Forest Baptist Medical Center

12. Association between metformin and cancer incidence and cancer mortality 33% in Cancer Mortality 31% in Cancer Incidence Wake Forest Baptist Medical Center Gandini, et al. Cancer Prev Res 2014;7:867-85

13. Cognitive Impairment and Dementia 45% 24% Campbell et al, J Alzh Dis 2018;65: 1225-38, Wake Forest Baptist Medical Center

14. Metformin and All-Cause Mortality metformin in type 2 diabetes vs. non-diabetics UKPDS NEJM 2008; 359:1577 Campbell et al. Aging Res Rev (2017) 30:31-44. .

15. Metformin and Age-Related Diseases Preliminary data from trials & observational studies Disease Prevention of type 2 diabetes ++++ Strength of association +++ ++ ++ ++ Prevention of CVD Prevention of cancer Prevention of dementia Reduction in mortality 20% MACE or mortality 31% incidence, 33% mortality 45% MCI, 24% AD Up to 28% vs not metformin Short-term exposure in not associated with long-term mortality benefit* Campbell et al. Aging Res Rev (2017) 30:31-44. Bannister et al. Diabetes, Obesity, Metabolism (2014) 16: 1165-1173. Gandini, et al. Cancer Prev Res 2014;7:867-85 Barzilai, et al. Cancer Prev Res 2014;7:867-85 *Lee et al. Cancer Diabetes Care 2021;44:2275 15 Wake Forest Baptist Medical Center

16. Diabetes Drug Use and COVID19 Mortality Ganesh & Randall Br J Clin Pharmacol 2022 88:2642 16 Wake Forest Baptist Medical Center

17. Diabetes Drug Use and Change in a Frailty Index: The LOOK Ahead Trial 17 Wake Forest Baptist Medical Center Simpson FR et al, Diabetes Care 2023 46:519

18. Other Outcomes Open-Angle Glaucoma < 40% Vergrosen et al JAMA Opthalmology 2022;140:674 Age-Related Macular Degeneration < 19% Liang, et al Invest Opthalmol Vis Sci 2022; 63:10 18 Wake Forest Baptist Medical Center

19. Summary Points A trial targeting aging to delay incidence of age- related disease is feasible and no larger than many other prevention trials. There is no single correct end-point. A trial with clear-cut clinical end-points is necessary to attract FDA interest and serve as an anchor for biomarker validation. 19 Wake Forest Baptist Medical Center