How Do you Grow Old Successfully Have Good

How Do you Grow Old Successfully? Have Good Genes in a Good Environment in Early Life. April 6, 2007 A. J. Kahn Berkeley, CA

Can single genes affect lifespan? 2 x Note: In the nematode gene manipulation has yielded animals that live 5 x longer! NIA/NIH - 2003

How heritable is human longevity? Genetic Heritability of Human Lifespan Cournil & Kirkwood 2001 Twin Studies Mc. Gue et al (1993) Herskind et al (1996) Ljungquist et al (1998) 0. 22 0. 25 <0. 33 Traditional Family Studies Philippe (1978) 0 -0. 24 Bocquet-Appel & Jakobi (1990) 0. 10 -0. 30 Mayer (1990) 0. 10 -0. 33 Gavrilova et al (1998) 0. 18 -0. 58 Cournil et al (2000) 0. 27 Genes account for 25% of what determines longevity

If genetics, per se, only play a 25% role in determining human longevity, then the balance of the critical factors affecting lifespan must reside in the environment. The Good News - much of our longevity (and healthy aging) is, at least potentially, under our control. Lifestyle choices - diet, preventive medicine, non-smoking, exercise, avoiding unsafe behavior.

Gene-environment Interactions are very important. Most birth defects (~65%) and probably most clinical problems arise as a consequence of gene-environment interaction. Chakravarti & Little, Nature 421, 2003

Caloric Restriction - the best established illustration of environmental intervention that affects longevity LE Magazine June 2003

An additional ‘take-home’ lesson Extended lifespan achieved by genetic alteration or environmental manipulation almost always equates, at least in a laboratory environment, to a reduced incidence potentially fatal diseases (e. g. cancer), slower onset of age-related senescent changes (loss in cognitive ability, slower mobility, greater fragility) and, of course, increased longevity. Concerns: impact on retirement infrastructure, medical care, workforce ‘turnover’, and economy.

Will CR work in Humans? Given the extended lifespan in humans, is it possible to answer this question?

Alternative Measures In many cases, ‘biomarkers’ (physiological/ or pathophysiologcal indicators of aging) are used instead of lifespan as a measure of a genetic or environmental effect on lifespan. Additionally, increased risk or incidence of conditions that predispose to higher morbidity and mortality will also be used as an indirect assessment of factors that affect healthy aging and likely longevity.

Some Candidate ‘Biomarkers’ * * Keep in mind for metabolic syndrome Heilbronn and Ravussin, 2003

Recent Findings Temperature Insulin Human study at 6 months post. Intervention. Heilbronn et. al. 2006

Something for the future? Caloric Restriction Mimetics: Agents that will duplicate or mimic the action of CR without the heavy, almost certainly unrealistic commitment to years of significant dieting. (A related strategy - use of oxidative damage control mimetics (e. g. , catalase/superoxide dismutase) that will augment natural resistance to oxidative stress and consequent damage. )

Is there a relationship between early development and aging and lifespan? Do events that occur in utero and early in postnatal life also affect lifespan? Might such events also increase the risk of morbidity in adult life and, therefore at least indirectly, longevity?

More Suggestive Evidence: Even Month of Birth May Affect Longevity Month of Birth Predicts the US Life Expectancy at Age 80 Computed using the Social Security Administration data Source: Gavrilova, N. S. , Gavrilov, L. A. Search for Predictors of Exceptional Human Longevity. In: “Living to 100 and Beyond” Monograph. The Society of Actuaries, Schaumburg, Illinois, USA, 2005, pp. 1 -49.

Multiple Factors May Affect Adult Disease Risk Gluckman and Hanson, 2004

Epigenetics (‘above the genome’): Circumstance in which gene function is altered stably but without fundamental change, e. g. , by mutation, deletion, rearrangement, in primary DNA structure. Epigenesis typically (always? ) occurs via alterations in chromatin structure (e. g. , modification in histone structure) or secondary changes in DNA, e. g. , DNA methylation). DNA methylation, for example, is associated with a reduction in gene expression.

DNA methylation Histone modification Hill, 2006

Vitamin supplements to mothers -> darker, smaller less obese pups (folic acid, vitamin B 12, choline and betaine -> increased DNA methylation. ) Cohen, 2003 after Jirtle

Changes in DNA methylation occur over a lifetime and help to explain the differences between identical twins and the divergence observed in individual humans and animals as they age. Fraga et. al. , 2005

Nutritional Factors Affecting Human Offspring Folate = folic acid Johnson-Zeigler, 2006

Postnatal diet can also affect lifespan Ozanne & Hales, 2004

Maternal; behavior Can Also Effect Epigenetic Change Increased grooming -. > altered DNA methylation/histone acetylation GC receptor In brain (hippocampus) ->altered stress resistance. Nature Neuroscience, 2004

The obesity epidemic

CDC

The problem only gets worse with age Age-specific prevalence of the metabolic syndrome among 8814 US adults U. Laval, 2004

Dutch Famine WW II Olson, 2004

Obesity as consequence of malnutrition in utero Olson, 2004

Barker Hypothesis Prenatal events establish lifelong physiological patterns that may manifest as disease processes in later life -David Barker, FRS, University of Southampton

The consequence of poor maternal malnutrition and the fetus is likely intrauterine growth retardation leading to low birth weight. Why is Low Birth Weight Important? • Prematurity- immature organ systems –In particular lungs- lack of surfactant • Leads to respiratory distress syndrome –Inadequate fat stores • Inability to maintain body temperature • Low birth weight for age- predisposition to cardiovascular disease, hypertension and NIDDM in adult life- concept of ‘intrauterine programming’ and the concept of the ‘thrifty hypothesis’. Olson, 2004

Some examples of effects low birth weight in adults Gluckman & Hanson. 2004

Still more examples G. M. England, 2003

The ‘Thrifty Phenotype” A ‘mismatch’ between the in utero ‘programming’ to conserve nutritional resources, e. g. fat storage, (as a consequence of poor maternal nutrition) and an abundance of food in postnatal life. Mc. Carthy, 1998

Lau & Rogers, 2004, Fetal Programming Metabolic syndrome is characterized by obesity, diabetes (insulin resistance) and an increased incidence of CVD.