2/12/2014 Young Aged LC3-II/Actin Ratio *** 1 0 + Chloro + - - PDF document

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2/12/2014 Young Aged LC3-II/Actin Ratio *** 1 0 + Chloro + - - PDF document

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2/12/2014 Young Aged LC3-II/Actin Ratio *** 1 0 + Chloro + Chloro B. Bruce Ito, Nandini Ravindran, Robert Mentzer, unpublished data 1 2/12/2014 HFD Chow p62 LC3 Normal Chow High Fat Diet (16 wk) Bruce Ito, Nandini Ravindran,

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B.

LC3-II/Actin Ratio

+ Chloro + Chloro 1

*** Young Aged

Bruce Ito, Nandini Ravindran, Robert Mentzer, unpublished data

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p62 LC3 Chow HFD High Fat Diet (16 wk) Normal Chow

Bruce Ito, Nandini Ravindran, Robert Mentzer, unpublished data

10 20 30 40 50 60 70 80 90 100 Infarct Size (% )

Chow (6) DIO (4) Deaths: Chow: 1 / 8 DIO: 4 / 7 Chengqun Huang, Bruce Ito, Robert Mentzer, unpublished data

  • Yucatan minipigs maintained for 4mo on

regular diet or high-fat, high-fructose diet

  • Subjected to experimental heart attack with or

without cardioprotective intervention

  • Measured autophagy markers and infarct size
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Bruce Ito, Robert Mentzer, unpublished data Bruce Ito, Robert Mentzer, unpublished data Bruce Ito, Robert Mentzer, unpublished data

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  • Atrial biopsies obtained before aortic

cross-clamp and after its removal

  • Patients undergoing CABG or valve repair
  • Tissue snap-frozen and assessed for

autophagy proteins by western blot

Jahania, colleagues, and Mentzer. J Am Coll Surg 2013

Atg5-12

0.0 0.2 0.4 0.6 0.8 1.0 Before After

p = 0.002

p62

0.0 0.1 0.2 0.3 0.4 0.5 Before After

p = 0.001

Beclin-1

Pt Sample 6a 6b 7a 7b 8a 8b 9a 9b

Atg5-12 p62 Actin Pt Sample 6a 6b 7a 7b 8a 8b 9a 9b 10a 10b 11a 11b 12a 12b

Actin

0.0 0.2 0.4 0.6 0.8 Before After

N.S.

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Risk Predictors

  • Age
  • Ejection fraction
  • Metabolic syndrome features

– Obesity – Hypercholesterolemia, dyslipidemia – Hyperglycemia, diabetes

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  • Mice were deprived of food for 24hr on

Monday and Thursday

  • Free access to food all other days
  • Compared to mice with free access to food

all seven days of the week

  • Enrolled at age 10mo (middle age) and

maintained for 1 year (old age, 22mo)

  • Evaluated Tmemory cells and severity of

injury after heart attack

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  • No difference in weight
  • More active in cage
  • Less hair loss
  • Higher levels of autophagy proteins
  • More naive T-cells (immunologic youth)
  • Better tolerance to myocardial infarction

Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet.

Hatori M, Vollmers C, Zarrinpar A, DiTacchio L, Bushong EA, Gill S, Leblanc M, Chaix A, Joens M, Fitzpatrick JA, Ellisman MH, Panda S. Cell Metab. 2012, 15:848-60.

After 100 days, the mice who ate fatty food throughout the day gained weight and developed high cholesterol, high blood glucose, liver damage and diminished motor control, while the mice who had access to the same fatty food for only 8 hours/day weighed 28% less and showed no adverse health effects despite consuming the same amount of calories from the same fatty food. The time- restricted mice also did better on an exercise test than the mice who ate either fatty food or normal chow throughout the day.

  • Autophagy is probably the key factor in

preventing age-related diseases

  • Overnutrition suppresses autophagy
  • Intermittent fasting shows promise for

preventing age-related diseases

  • But we don’t know how much is enough, AND,
  • We need better tools to monitor autophagy in humans
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Mridula Ramesh Moutusee Islam Diana Lui Xinghao Zhang Jon Sin Allen Andres Chengqun Huang Jen Ramil Rick Sayen Robert Mentzer, Jr. Bruce Ito Nandini Ravindran Salik Jahania David Sengstock Peter Vaitkevicius Phyllis-Jean Linton Michael Gurney

Support from

NIH P01-HL112730, R01-HL60590, R01-AG33283, R01-HL34579, R01-HL92136

Reagents from

Tamotsu Yoshimori Richard Youle William Claycomb Allen Andres Allen Andres Genaro Genaro Hernandez Hernandez Yoshimi Yoshimi Hiraumi Hiraumi Chengqun Chengqun Huang Huang Moutusee Moutusee Islam Islam Pamela Lee Pamela Lee Giovanni Giovanni Quarato Quarato Bruno Bruno Queliconi Queliconi Mridula Mridula Ramesh Ramesh Jen Ramil Jen Ramil Rick Rick Sayen Sayen Jon Jon Sin Sin David Taylor David Taylor Ying Ying Xiong Xiong Xinghao Xinghao Zhang Zhang Robert Mentzer, Jr. Robert Mentzer, Jr. Bruce Ito Bruce Ito Salik Salik Jahania Jahania Nandini Nandini Ravindran Ravindran David David Sengstock Sengstock Peter Peter Vaitkevicius Vaitkevicius Phyllis Phyllis-Jean Linton Jean Linton Michael Gurney Michael Gurney

Support from

NIH P01-HL112730 NIH R01-HL034579 NIH R01-HL060590