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

2. Age and Sex Specific Mortality Rates

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

4. Weight (lb) Death from CHD At birth Before 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 Development Origins of Health and Disease - Coronary Heart Disease and Early Weight 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. … while on the other hand … The Importance of Early Life

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

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

9. The “Disposable Soma” Kirkwood Nature 1977 Aging – Historically a Rarity, Now Routine 1900 2000 20804060 Age

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

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

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

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

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

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

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

20. Factors Influencing Health Trajectories in Old Age nGenes nNutrition nLifestyle nEnvironment nSocioeconomic status nAttitude

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. Trichopoulou A et al. (2005) BMJ 330, 991-997 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

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

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

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

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

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

29. Key Questions About Early Interventions 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?

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

31. Progeny Growth Maintenance and Repair Storage Reproduction Etc … ORGANISM Resources 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). Metabolism and Nutrient Availability Influence Resource Allocation

32. Early Interventions – Prospects and Challenges nNutrition and lifestyle nEducation and attitude nPotential biological targets nMeasurement – biomarkers nRegulation nEthics

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 ShanleyClaudio Franceschi (Bologna) Thomas von ZglinickiEline Slagboom (Leiden) Doug TurnbullKaare Christensen (Odense) Laura GreavesRudi 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 “100 th ” birthday