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

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

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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

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To impr prove heal alth an and qu d qual ality o

  • f l

f life fe for old

  • r 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

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

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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

  • f tr

traditional clin linic ical t l tria rial l appro roaches

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SLIDE 6

Lopez-Otin et al, Cell 2013

Biolog

  • gic Progr

gres ess in Agi Aging

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SLIDE 7

Biol

  • log
  • gica

cal A Aging Mitocho hondr ndrial decline ne DNA A Meth thyla lati tion Apop

  • p/Necrop

croptos

  • sis

↑ Senescent C t Cells lls ↑ Altered a d autophag phagy Dise sease ses Depre ression

  • n

Cogniti tive D Declin line Cancer Chronic I c Infect ction Cardi diova vasc scul ular ar Diabe abetes/ s/Obe besi sity Depe pend ndenc nce Disabi sability Multi ltiple le Dise sease ses Morta tality ity

Potential T Trig riggers rs Clin linic ically ly A Appa ppare rent

Outc tcom

  • mes

Genetic tic V Varia iati tion Environme ment

FRAILT LTY

Physiol

  • log
  • gy

↑Infla lammatio tion ↑ Angiotens nsin n system a em action ↑ HPA A Axis xis ↑ Sympat pathe hetic nerv rvou

  • us

system em ↓ Decreased ener ergy produc duction Weakne ness ss Fatig igue Weight los loss Slown wness

Driv ivers rs of Frailt ailty y and Advers rse Ou Outc tcom

  • mes

es in Ol Older Ad Adults

Wals lston J J, , 2016

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 Complexity is enor

  • rmo

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

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 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

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Biol

  • log
  • gica

cal A Aging Mitocho hondr ndrial decline ne DNA A Meth thyla lati tion Apop

  • p/Necrop

croptos

  • sis

↑ Senescent C t Cells lls ↑ Altered a d autophag phagy Dise sease ses Depre ression

  • n

Cogniti tive D Declin line Cancer Chronic I c Infect ction Cardi diova vasc scul ular ar Diabe abetes/ s/Obe besi sity Depe pend ndenc nce Disabi sability Multi ltiple le Dise sease ses Morta tality ity

Potential T Trig riggers rs Clin linic ically ly A Appa ppare rent

Outc tcom

  • mes

Genetic tic V Varia iati tion Environme ment

FRAILT LTY

Physiol

  • log
  • gy

↑Infla lammatio tion ↑ Angiotens nsin n system a em action ↑ HPA A Axis xis ↑ Sympat pathe hetic nerv rvou

  • us

system em ↓ Decreased ener ergy produc duction Weakne ness ss Fatig igue Weight los loss Slown wness

Driv ivers rs of Frailt ailty y and Advers rse Ou Outc tcom

  • mes

es in Ol Older Ad Adults

Wals lston J J, , 2015

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Lopez-Otin e n et al, C Cell 2013

Tra Tradit itio ional l Tre Treatment Develo lopment Appro roaches

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Inflammation SNS HPA Axis

Chronic Disease Disability Depression

St Stre ress Response Sy Systems and d De Decline

Angiotensin System

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  • Angiotensin Receptor Blockers ARBs)

(target mitochondrial dysfunction, mitophagy, and muscle decline)

  • Anti-inflammatory agents… may help

slow accelerated apoptosis/necroptosis and senescent cell proliferation

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Losartan

AngI AngII

ACE

ATR1 ATR2 pSmad2/3 pERK TGF-β signaling Fibrosis Fibrosis Fibrosis MRFs Myoblast proliferation Satellite Cell Activation

Inflammation, dysfunctional mitochondria

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5 10 15 20 25 30

Control Placebo Losartan

Percent of Fibrosis

***

Placebo Losartan Control

1 2 3 4

Placebo Losartan

Tetanic/Twitch Ratio

* *

Burks et al., 201

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10 20 30 40 50 60 70

Normalized TA Weight

** 5 10 15 20 25 30 35

Myofibers (102)

**

Placebo Losartan

Control Placebo Losartan

C = Contralateral I = Immobilized

Control Placebo Losartan

C I C I C I C I

Burks et al., 201

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SLIDE 17

 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

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 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)

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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

  • n Agin

ging, P P30-AG021334 021334 Biolo iology of

  • f H

Healt lth A Agin ging Prog rogram Div Divis ision of

  • f 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