Systems Biology of Human Aging:  An ecological perspective on the roles of inflammation and nutrition

Systems Biology of Human Aging: An ecological perspective on the roles of inflammation and nutrition PowerPoint PPT Presentation

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. . . nutrition therapeutic drugsinfectionsinflammogens air pollution toxinsstress physical socialpositive social interactions. . The Gero-Inflammatory Manifold. External Environment. Internal environment . . Chronic inflammatory processes are ubiquitous during adult aging.

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Systems Biology of Human Aging: An ecological perspective on the roles of inflammation and nutrition

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3. Chronic inflammatory processes are ubiquitous during adult aging progressive postnatal changes monocyte activation: artery, brain, lung, oxidatively damaged elastin and matrix proteins that attract monocytes later ages increased blood CRP and IL-6 increased proinflammatory gene expression in most tissues T cell senescence

4. Long-lived proteins accumulate damage

5. Molecular and cell aging

6. aorta - aging of irreplaceable elastin damage from glucose and inflammation Fornieri C, Arterioscler Thromb 1992 ; Finch CE, 2007, p.17

7. Shared inflammatory processes in normal aging and diseases active macrophages/monocytes local oxidative damage from free radicals

8. Arterial lesions are active at birth

9. Shared inflammatory mechanisms in atherosclerosis and Alzheimer disease?

10. Chronic infection and inflammation increase risk of Arterial disease ++ Alzheimer disease + Some cancers +++ (GI tract, Helicobacter pylori)

11. Hypothesis: diet and inflammation are major factors in the human lifespan by influencing the progression of atherosclerosis, cancer, and Alzheimer disease

12. interactions of oxidative stress and inflammmation bystander damage from oxidative stress stimulates inflammatory processes inflammation causes bystander damage Nutritional influences on bystander damage

13. Diet restriction attenuates amyloid deposits -35% ad lib/ 4 mo familial Alzheimer transgenic mice NV Patel et al, Neurobiol Aging, 2005

14. Caloric restriction of lab rodents slows most aspects of aging Slows mortality acceleration rate constant (Gompertz slope) attenuates strain specific organ degeneration Attenuates systemic and tissue oxidative damage Attenuates inflammatory gene expression Impairs wound healing and some adaptive immune responses

15. Anti-inflammatory drugs & statins protect against many chronic diseases of aging

16. Ibuprofen in ad lib diet attenuates brain amyloid deposits APPswe/ind familial AD mouse TE Morgan CE Finch; 2004

17. Coronary risks associate with the # of different infections (seropositivities, CMV, EBV, HSV1 , C Pneumoniae, H Pylori, H influenzae) Zhu et al Am J Cardiol: 2000

18. AIDS induces brain amyloid Abeta- containing ‘diffuse plaques’ in frontal cortex; Rempel HC AIDS 19: 127; 2005

19. Long-term air pollution exposure accelerates markers of brain aging young adults: Mexico City vs Veracruz Calduron-Garciduenas et al Toxicol Pathol 2008 disrupted blood-brain barrier ultrafine carbon particles in brain olfactory neurons 8-OHG in neurons activated microglia and astrocytes in cerebral cortex: NFkB, COX-2 induction accumulated amyloid ß-42/?-synuclein

20. Diffuse amyloid Aß42 deposits in brains of Mexico City (MxC) vs control city(CTL) young adults: E3, apoE3; E4, apoE4

21. Aging increases IL-6 in mixed glia Xie et al, Exp Neurol 2003

22. neuron stem cell survival in primary culture is lower with aging astrocytes

24. Historical increases of life expectancy Oepen and Vaupel, Science 2002; C Finch adaptation

25. Walt Whitman at 45 “I am in good spirits – only getting old - most 50, you know.” (letter, Feb 12, 1867)

26. Hypothesis of historical increase in lifespan, 1750 to present Finch & Crimmins, Science 2004, PNAS 2006 aging has slowed Improved diet and hygiene decreased infections 1750-1900 decreased infection and inflammation slowed aging vaccination (1890); antibiotics (1950)

27. Infant mortality & heart disease in Norway by cohort 40-69 yr later survivors in cohorts with high infant mortality ‘carry life-long vulnerability’ Forsdahl A Brit J Prevt Social Med 31: 91-95 1977

28. Mortality in Sweden 1751-1940 birth cohort vs historical period Finch & Crimmins, Science 2004, 2005; PNAS 2006

29. Cohort mortality in Sweden 1751-1940 “cohort morbidity phenotype” same slope but different intercepts demographic aging is increasingly delayed

30. Inflammatory hypothesis of the historical increase of human life spans

31. Adult height increased inversely with infant mortality in 19th C Sweden and France Crimmins and Finch PNAS 2006

32. Resource allocation

33. Minimum mortality qmin: the lowest mortality rates are observed at puberty portion of the mortality curve between the descending early mortality and ascending mortality acceleration associated with senescence (Gompertz curve). levels and duration of qmin indicate the onset of senescence (Gompertz acceleration) qmin may estimate lifespans in the absence of senescence Minimum mortality qmin calculation of potential lifespan

34. qmin chimps vs hunter-gatherers

35. qmin, cohorts, 4 Countries, 1751-1989 CHART SOURCE: FIG. 2A, Engl-Swe-Switz-USA_min_qx_ages 0-20_M+F.xls NOTES…CHART SOURCE: FIG. 2A, Engl-Swe-Switz-USA_min_qx_ages 0-20_M+F.xls NOTES…

36. Hypothetical lifespan in absence of aging with constant qmin If subadult qmin were maintained indefinitely, survival curves would be described by 0th order kinetics, like radioactive decay: N/No = exp(qmin)time Median lifespan = half-life or ln2/qmin Sweden 1751, qmin 0.006; median ,115 y Sweden 1998, qmin 0.000 03; median 23,000 y

37. 1985 Obesity

38. 1995 Obesity

39. 2001 Obesity

40. Russian longevity crash - will other nations follow?

41. Opposing changes in the future of longevity

42. determinants of individual aging I, inherited genetic differences II, random cell variations during development III, somatic cell DNA damage during aging IV, somatic cell damage from environment: infection, inflammation, pollution, nutrition, stress III-IV random hits during aging create individual mosaics of diverse tissue differences potential interventions diet-drugs to slow inflammation and oxidative damage regenerative medicine at level of gene regulation for control of molecular lifespan and cell regeneration

43. We don’t know the future of the human life span

44. Synaptic changes are concurrent with progressive increases of astrocytic volume and GFAP expression during normal aging, in absence of amyloid accumulation (rodent) or in absence Alzheimer disease (human). Hypothesis: age increase of GFAP as a factor in synaptic regression during aging

45. E18 neurite outgrowth in heterochronic cultures of astrocytes: young (3 mo) > old (24 mo)

46. age impairment of neurite outgrowth reversed by SiRNA diminution of GFAP in old astrocytes

47. Atheromas are hot In vivo thermography of atherosclerotic plaques A, control rabbit B, cholesterol-fed 3 mo atheroma+1oC C. 3 mo return diet Verheye S Circulation 2002

48. Chronic diseases of aging begin early Fetal arteries microscopic atheromas Atherosclerosis accelerated by environment Mild brain inflammation and neuronal atrophy by age 50; *extreme development in Alzheimer’s environmental effects in Alz implied

49. Biochemistry of aging free radicals cause oxidative damage unpaired electron chemically oxidizes and combines with proteins, lipids, DNA (mutations) superoxide, hydrogen peroxide, nitric oxide Glucose causes oxidative damage (glyco-oxidation) spontaneous reaction that chemically oxidizes and combines with proteins, lipids, DNA

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