How Do you Grow Old Successfully?Have Good Genes in a Good Environment in

EarlyEarly Life.

April 6, 2007A.J. KahnBerkeley, CA

NIA/NIH - 2003

Can single genes affect lifespan?Can single genes affect lifespan?

Note: In the nematode gene manipulation hasyielded animals that live 5x longer!

2x

Genetic Heritability of Human LifespanCournil & Kirkwood 2001

Twin StudiesMcGue et al (1993) 0.22

Herskind et al (1996) 0.25Ljungquist et al (1998) <0.33

Traditional Family StudiesPhilippe (1978) 0-0.24

Bocquet-Appel & Jakobi (1990) 0.10-0.30Mayer (1990) 0.10-0.33Gavrilova et al (1998) 0.18-0.58

Cournil et al (2000) 0.27

Genes account for 25% of what determines longevity

How heritable is human longevity?How heritable is human longevity?

If genetics, per se, only play a 25% role in determiningIf genetics, per se, only play a 25% role in determininghuman longevity, then the balance of the critical factorshuman longevity, then the balance of the critical factorsaffecting lifespan must reside in the affecting lifespan must reside in the environmentenvironment..

The Good NewsThe Good News - much of our longevity (and healthy aging) - much of our longevity (and healthy aging)is, at least potentially, under our control.is, at least potentially, under our control.

Lifestyle choices - diet, preventive medicine, non-smoking,Lifestyle choices - diet, preventive medicine, non-smoking,exercise, avoiding unsafe behavior. exercise, avoiding unsafe behavior.

Chakravarti & Little, Nature 421, 2003

Most birth defects (~65%) and probably most clinical problems arise as a consequence of gene-environment interaction.

Gene-environment Interactions areGene-environment Interactions are very important.very important.

LE Magazine June 2003

Caloric Restriction - the best established illustration of environmental Caloric Restriction - the best established illustration of environmental intervention that affects longevityintervention that affects longevity.

Extended lifespanExtended lifespan achieved by genetic alteration orenvironmental manipulation almost always equates, atleast 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:Concerns: impact on retirement infrastructure, medical care, workforce ‘turnover’, and economy.

An additional ‘take-home’ lessonAn additional ‘take-home’ lesson

Will CR work in Humans?Will CR work in Humans?

Given the extended lifespan in humans,is it possible to answer this question?

Alternative Measures 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.

Heilbronn and Ravussin, 2003

*

* Keep in mind for metabolic syndrome

Some Some CandidateCandidate‘‘Biomarkers’Biomarkers’

Heilbronn et. al. 2006

Human study at6 months post-Intervention.

TemperatureTemperature

InsulinInsulin

Recent FindingsRecent Findings

Caloric Restriction Mimetics: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.)

Something for the future?Something for the future?

Do events that occur in utero and early inpostnatal life also affect lifespan?

Might such events also increase the risk ofmorbidity in adult life and, therefore at least indirectly, longevity?

Is there a relationship between early development andIs there a relationship between early development and aging and lifespan?aging and lifespan?

Month of Birth

Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec

life expectancy at age 80, years7.6

7.7

7.8

7.9

1885 Birth Cohort1891 Birth Cohort

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.

More Suggestive Evidence:More Suggestive Evidence: Even Month of Birth May Affect Longevity

Gluckman and Hanson, 2004

Multiple Factors May Affect Adult Disease RiskMultiple Factors May Affect Adult Disease Risk

EpigeneticsEpigenetics (‘above the genome’): Circumstance in which gene function is altered stably but without fundamental change, e.g.,by mutation, deletion, rearrangement, in primaryDNA structure.

EpigenesisEpigenesis 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.

Hill, 2006

DNA methylation

Histone modification

Cohen, 2003 after Jirtle

Vitamin supplements to mothers -> darker, smallerless obese pups (folic acid, vitamin B12, choline and betaine ->

increased DNA methylation.)

Fraga et. al., 2005

Changes in DNAmethylation occurover a lifetime andhelp to explain the differences between identical twins and the divergence observed in individual humans and animals as they age.

Johnson-Zeigler, 2006

Nutritional Factors Affecting Human OffspringNutritional Factors Affecting Human Offspring

Folate = folic acid

Ozanne & Hales, 2004

Postnatal diet can also affect lifespanPostnatal diet can also affect lifespan

Nature Neuroscience, 2004

Increased grooming -.> altered DNA methylation/histone acetylation GC receptor In brain (hippocampus) ->altered stress resistance.

Maternal; behavior Can Also Effect Epigenetic ChangeMaternal; behavior Can Also Effect Epigenetic Change

The obesity epidemicThe obesity epidemic

CDC

The problem only gets worse with ageThe problem only gets worse with age

Age-specific prevalence of the metabolic syndrome among 8814 US adults

U. Laval, 2004

Dutch Famine -Dutch Famine -WW IIWW II

Olson, 2004

Olson, 2004

Obesity as consequence of malnutrition in uteroObesity as consequence of malnutrition in utero

Prenatal events establish lifelong physiological patterns that may manifest

as disease processes in later life

-David Barker, FRS, University of Southampton

Barker HypothesisBarker Hypothesis

The consequence of poor maternal malnutrition and The consequence of poor maternal malnutrition and the fetus is likely intrauterine growth retardation the fetus is likely intrauterine growth retardation leading to low birth weight.leading to low birth weight.

•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’.

Why is Low Birth Weight Important?Why is Low Birth Weight Important?

Olson, 2004

Gluckman & Hanson. 2004

Some examples of effects low birth weight in adultsSome examples of effects low birth weight in adults

G.M. England, 2003

Still more examplesStill more examples

McCarthy, 1998

A ‘mismatch’ betweenthe in utero ‘programming’ to conserve nutritionalresources, e.g. fat storage,(as a consequence of poormaternal nutrition) and anabundance of food in post-natal life.

The ‘Thrifty Phenotype”The ‘Thrifty Phenotype”

Lau & Rogers, 2004,Fetal Programming

Metabolic syndromeMetabolic syndrome is characterized by obesity, diabetes(insulin resistance) and an increased incidence of CVD.