Early Interventions Tom Kirkwood Institute for Ageing and Health Newcastle University

1. New York Academy of Medicine & Royal Society of Medicine Promoting Health in Aging 26-27 September 2011 Early Interventions Tom KirkwoodInstitute for Ageing and HealthNewcastle University

2. Age and Sex Specific Mortality Rates

3. The Importance of Early Life On the one hand …

4. Development Origins of Health and Disease - Coronary Heart Disease and Early Weight Weight (lb) Death from CHD At birthBefore 65 years All ages <5.5 1.50 (0.98–2.31) 1.37 (1.00–1.86) -6.5 1.27 (0.89–1.83) 1.29 (1.01–1.66) -7.5 1.17 (0.84–1.63) 1.14 (0.91–1.44) -8.5 1.07 (0.77–1.49) 1.12 (0.89–1.40) -9.5 0.96 (0.66–1.39) 0.97 (0.75–1.25) -9.5 1.00 1.00 P for trend 0.001 0.005 Age 1 year <18 2.22 (1.33–3.73) 1.89 (1.34–2.66) -20 1.80 (1.11–2.93) 1.58 (1.15–2.16) -22 1.96 (1.23–3.12) 1.66 (1.23–2.25) -24 1.52 (0.95–2.45) 1.36 (1.00–1.85) -26 1.36 (0.82–2.26) 1.29 (0.93–1.78) >27 1.00 1.00 P for trend <0.001 <0.001 Barker et al Lancet 1989

5. Persistent epigenetic differences associated with prenatal exposure to famine in humans Heijmans et al PNAS 2008 • Individuals prenatally exposed to famine during the Dutch Hunger Winter in 1944-5 have less DNA methylation of the imprinted IGF2 gene. • The association was specific for peri-conceptional exposure. • Early-life environmental conditions can cause epigenetic changes in humans that persist throughout life.

6. The Importance of Early Life … while on the other hand …

7. Period and Cohort Effects on Japanese Mortality Mortality Declines Driven Mainly by Improvements in Late Life Engelaer et al, 2011

8. What drives aging? When does it begin? What factors modulate healthy longevity? How to define the elusive boundary between aging and disease? How and when to intervene? Aging Begins Early But How Early and Why?

9. 20 40 60 80 Age The “Disposable Soma” Kirkwood Nature 1977 Aging – Historically a Rarity, Now Routine 1900 2000

10. ORGANISM Resources Growth Maintenance and Repair Storage Reproduction Etc … Progeny The Central Role of Resource Allocation in Biological Evolution Kirkwood (1981) in Physiological Ecology: An Evolutionary Approach to Resource Use (eds Townsend & Calow)

11. INFLAMMATION ANTI-INFLAMM. GOODLIFESTYLE GOODFOOD STRESS BADFOOD ENVIRONMENT AGING PROCESS AND ITS MALLEABILITY Kirkwood Cell 2005 Age-related Frailty, Disability, and Disease Accumulation of Cellular Defects Random Molecular Damage

12. What drives aging? DAMAGE When does it begin? What factors modulate healthy longevity? How to define the elusive boundary between aging and disease? How and when to intervene? Key Questions About Early Interventions

13. Damage Accumulates From Day One Each cell division is accompanied by inevitable somatic mutation

14. Age-Related Increase in Frequency of Hprt Mutations in Mice Senescence- accelerated mice (SAM) Wild-type Odagiri et al Nat Genet 1998

15. Copying errors, Telomere shortening ROS, etc Mutations e.g. ROS DNA ROS ATP Transcription errors mtDNA RNA Translation errors ROS ATP Damage, denaturing e.g. ROS PROTEIN Refolding Antioxidants Chaperones Degradation or aggregation (e.g.b-amyloid) The Deep Mechanisms of Aging

16. Mitochondrial Mutations in Human Colon Taylor et al J Clin Invest 2003

17. Telomere Erosion, Stress and Health • Telomeres protect chromosome ends – they shorten with cell division and this is accelerated by biochemical stress. • Prematurely short telomeres are linked with increased risk of age-related disease and diminished survival. • People suffering severe chronic stress (eg carers of those with dementia and other conditions) have shorter telomeres.

18. Senescent Cell (human fibroblast) • DNA damage foci • Telomeres • Overlap of damage foci with telomeres • Mitochondria with high membrane potential • Mitochondria with low membrane potential

19. What drives aging? DAMAGE When does it begin? EARLY What factors modulate healthy longevity? How to define the elusive boundary between aging and disease? How and when to intervene? Key Questions About Early Interventions

20. Factors Influencing Health Trajectories in Old Age Genes Nutrition Lifestyle Environment Socioeconomic status Attitude

21. Heritability of Human Longevity - Twin Studies Coefficient of heritability McGue et al (1993) 0.22 Herskind et al (1996) 0.25 Ljungquist et al (1998) <0.33 Genes account for about 25% of what determines longevity

22. Nutrition and Survival: EPIC-Ageing Study 76,707 men and women aged 60+ No CHD, stroke or cancer at enrolment Median follow up 89 months (4047 deaths) Adherence to Mediterranean diet assessed on 10-point scale: 0 (poor)…9 (high) 2 unit increment results in 8% reduction of overall mortality Trichopoulou A et al. (2005) BMJ330, 991-997

23. A few minutes on the Metro, a few years … 66.1 71.5 70.1 63.8 Ponteland South 74.8 68.0 Age for expected onset of limiting long-term condition for 55 yr old person Courtesy Prof Peter Gore/Prof Carol Jagger/ONS

24. Intrinsic Ageing is Hugely Variable, Influenced but not Controlled by Genes, Environment, EtcKirkwood & Finch Nature 2002 Wild type Age-1 mutation

25. What drives aging? DAMAGE When does it begin? EARLY What factors modulate healthy longevity? MANY How to define the elusive boundary between aging and disease? How and when to intervene? Key Questions About Early Interventions

27. Disease count No One Has Perfect Medical Health at Age 85 Newcastle 85+ Study Collerton et al British Medical Journal 2009

28. Disease B Disease C Likely Effectiveness of Interventions Mechanisms Underlying Age-Related Disease Accumulation of Molecular and Cellular Damage Disease A End-Stage Pathology Initiating Processes

29. What drives aging? DAMAGE When does it begin? EARLY What factors modulate healthy longevity? MANY How to define the elusive boundary FURTHER between aging and disease? STUDY OF DAMAGE How and when to intervene? Key Questions About Early Interventions

30. The Importance of Trade-Offs Longevity Factors promoting growth/reproduction Factors promoting survival Is resource allocation affected by nutrient availability?

31. ORGANISM Resources Growth Maintenance and Repair Storage Reproduction Etc … Progeny Metabolism and Nutrient Availability Influence Resource Allocation • Insulin/IGF-1 signalling promotes growth and storage. • Low insulin/IGF-1 promotes cell maintenance. • Low nutrient levels reduce reproduction and promote maintenance (in short-lived species).

32. Nutrition and lifestyle Education and attitude Potential biological targets Measurement – biomarkers Regulation Ethics Early Interventions – Prospects and Challenges

33. Government Office for Science - Foresight: Mental Capital and Wellbeing Project. “Mental Capital Through Life: Future Challenges”, Kirkwood et al 2008

34. Thanks to: Daryl Shanley Claudio Franceschi (Bologna) Thomas von Zglinicki Eline Slagboom (Leiden) Doug Turnbull Kaare Christensen (Odense) Laura Greaves Rudi Westendorp (Leiden) Glyn Nelson Joao Passos Carole Proctor Joanna Collerton Karen Davies John Bond Carol Jagger Louise Robinson

35. “If I’d known I was going to live this long, I’d have taken better care of myself” US musician Eubie Blake on his “100th” birthday