To impr prove heal alth an and qu d qual ality o of l f life - PowerPoint PPT Presentation

To impr prove heal alth an and qu d qual ality o of l f life fe for old or older a adult ults To extend nd healthy hy, h high ghly f ly functiona ional, l, and nd cog cogni nitiv ively inta intact t lif lifespan

 Chronic Illness/Multimorbidity  Frailty  Functional decline  Cognitive decline  Vulnerability to acute illness

Not d t disease s specific Sp Specifi fic c biologic t c targets/r ts/rece ecepto tors no not al t alwa ways k kno nown Requi uires r rethi thinking ng o of tr traditional clin linic ical t l tria rial l appro roaches

Biolog ogic Progr gres ess in Agi Aging Lopez-Otin et al, Cell 2013

Driv ivers rs of Frailt ailty y and Advers rse Outc Ou tcom omes es in Ol Older Ad Adults Potential T Trig riggers rs Physiol olog ogy Outc tcom omes Clin linic ically ly A Appa ppare rent Biol olog ogica cal A Aging Mitocho hondr ndrial decline ne DNA A Meth thyla lati tion ↑ Infla lammatio tion Apop op/Necrop croptos osis ↑ Senescent C t Cells lls ↑ Angiotens nsin n ↑ Altered a d autophag phagy system a em action Weakne ness ss ↑ HPA A Axis xis Depe pend ndenc nce Fatig igue ↑ Sympat pathe hetic Disabi sability Genetic tic V Varia iati tion nerv rvou ous FRAILT LTY Weight Multi ltiple le Environme ment system em los loss Dise sease ses ↓ Decreased Morta tality ity ener ergy Slown wness Dise sease ses produc duction Depre ression on Cogniti tive D Declin line Cancer Chronic I c Infect ction Wals lston J J, , 2016 Cardi diova vasc scul ular ar Diabe abetes/ s/Obe besi sity

 Complexity is enor ormo mous  Complexity and comorbidities are daunting and make experimental design difficult  Heterogeneity between individuals is great, which make translation from homogenous animal models more difficult

 ENERGISE- Marco Pahor, U Florida  TAME Design and Rationale, Stephen Kritchevsky, Wake Forest  Prevention Trials in Older Persons, Dave Reuben, UCLA  Discussion: Evan Hadley, NIA; Jeremy Walston, Johns Hopkins

Driv ivers rs of Frailt ailty y and Advers rse Outc Ou tcom omes es in Ol Older Ad Adults Potential T Trig riggers rs Physiol olog ogy Outc tcom omes Clin linic ically ly A Appa ppare rent Biol olog ogica cal A Aging Mitocho hondr ndrial decline ne DNA A Meth thyla lati tion ↑ Infla lammatio tion Apop op/Necrop croptos osis ↑ Senescent C t Cells lls ↑ Angiotens nsin n ↑ Altered a d autophag phagy system a em action Weakne ness ss ↑ HPA A Axis xis Depe pend ndenc nce Fatig igue ↑ Sympat pathe hetic Disabi sability Genetic tic V Varia iati tion nerv rvou ous FRAILT LTY Weight Multi ltiple le Environme ment system em los loss Dise sease ses ↓ Decreased Morta tality ity ener ergy Slown wness Dise sease ses produc duction Depre ression on Cogniti tive D Declin line Cancer Chronic I c Infect ction Wals lston J J, , 2015 Cardi diova vasc scul ular ar Diabe abetes/ s/Obe besi sity

Tra Tradit itio ional l Tre Treatment Develo lopment Appro roaches Lopez-Otin e n et al, C Cell 2013

St Stre ress Response Sy Systems and d De Decline Chronic Disease Angiotensin Inflammation System SNS HPA Axis Disability Depression

 Angiotensin Receptor Blockers ARBs) (target mitochondrial dysfunction, mitophagy, and muscle decline)  Anti-inflammatory agents… may help slow accelerated apoptosis/necroptosis and senescent cell proliferation

AngI ACE AngII ATR2 Losartan Inflammation, dysfunctional ATR1 mitochondria TGF- β signaling pSmad2/3 pERK Fibrosis Fibrosis Fibrosis MRFs Satellite Cell Myoblast Activation proliferation

Control Losartan Placebo 30 4 Percent of Fibrosis * * Tetanic/Twitch 25 3 20 Ratio *** 15 2 10 1 5 0 0 Placebo Losartan Control Placebo Losartan Burks et al ., 201

Placebo Losartan 70 35 60 Normalized TA ** 30 Myofibers (10 2 ) 50 Weight 25 40 ** 20 30 15 20 10 10 5 0 0 C I C I C I C I Control Placebo Losartan C = Contralateral Control Placebo Losartan I = Immobilized Burks et al ., 201

 Embrace complexity and heterogeneity and figure out how to incorporate it into research strategies  Develop multidisciplinary teams within and across institutions that focus on translation  Ensure that all trainees engaged in aging research have multidisciplinary and translational education

 Pick Low Hanging Fruit ◦ Increase focus on dysregulated physiological systems already known to broadly impact health and well being ◦ Develop preventive strategies that target dysregulated physiological systems (inflammation, RAS, SNS, HPA axis)

Cl Clau aude e D. Pep epper er Ol Older er A Amer ericans I Indepen endence e Cen Center er Na Natio tional I Instit itute on on Agin ging, P P30-AG021334 021334 Biolo iology of of H Healt lth A Agin ging Prog rogram Div Divis ision of of G Geria riatri ric M Medi dicin ine a and G d Gero rontology Johns Hopkins B Bayv ayview ew M Med edical Cen Center er