Aging: What causes it What slows it

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Aging What causes it?What slows it?
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First experiments

• Osborne, Mendel, Ferry 1917

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Osborne, Mendel, Ferry 1917

• First scientific experiment suggesting that
  caloric restriction could extend lifespan
• During experiments on nutrition, selected rats
  were fed a calorie restricted diet ("stunted")
  over various period of time.
• Normally-fed rats mortality rate (91 rats total)
• 17 (19) lt 1yr.
• 48 (53) lt 2 yrs.
• 26 (29) gt 2 yrs.

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Four calorie restricted females

• More than 2/3 of stock rats die within 2 yrs.
• All 4 stunted females lived longer than 2 years.
• All four were breeding at a time when rats are
  typically in menopause.
• They produced from 3 to 6 litters all as
  vigorous as offspring from younger mothers.
• Sample size (4 rats) was insufficient to give a
  statistically significant demonstration.

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• Osborne knew he couldnt make any firm
  conclusions from an experiment with only four
  rats. But he thought the observation was
  interesting and published it in the journal
  Science (which Thomas Edison had founded a few
  years earlier). In that Science article Osborne
  said, it appears as if the preliminary stunting
  period lengthened the total span of their life.
• That same year, J. Northrop showed that he could
  extend the lifespan of fruit flies when he
  restricted their food intake during the larval
  stage.

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Caloric restriction results replicated in other
species
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Spider life span

• Normal diet average 50 days maximum 100 days
• Caloric restriction average 90 days maximum
  139 days

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Single cell organism lifespan

• Normal diet average 7 days maximum 14 days
• Caloric restriction average 13 days maximum
  25 days

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Guppy life span

• Normal diet average 33 months maximum 54
  months
• Caloric restriction average 46 months maximum
  59 months

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Rat lifespan

• Normal diet average 23 months maximum 33
  months
• Caloric restriction average 33 months maximum
  47 months

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Calorie Restriction in Rhesus Monkeys

• Mattison, Lane, Roth, Ingram

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Methods

• Typical average life span of rhesus macaques
  estimated at 25 years.
• In 1987 National Institute on Aging began study
  of 30 CR in male and female rhesus macaques of
  1-17 years of age.
• Range of ages allowed assessment of CR on various
  age groups.
• Number of animals was eventually 60 of each sex.

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CR effect on rhesus lifespan and disease

• Preliminary mortality data are not yet
  statistically significant, but indicate that
  mortality to date is lower in CR animals (15)
  than in controls (24).
• The CR group has lower incidence of chronic
  diseases including cancer, cardiovascular
  disease, diabetes, endometriosis, fibrosis,
  amyloidosis, ulcers, cataracts and kidney failure.

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CR lowers abdominal fat
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Biomarkers

• A biomarker for aging is a measurement that
  predicts survival.
• Could help to reduce cost and time involved in
  evaluation of anti-aging interventions.
• There is debate over what constitutes a marker
  and how it should be evaluated.
• That aside, the following are some candidates.

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Body temperature

• CR over 6 years reduced colonic body temperature
  about 0.5 Celsius.
• This agrees with rodent studies.
• Is consistent across age range of 7-13 years.
• Additional test using implanted thermometers
  using radio telemetry for 24 hr monitoring.
• Temperature decreased as food intake reduced.
• At 30 restriction, temp was significantly
  (plt0.003) lower than controls group.
• Circadian patterns were maintained.

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CR lowers body temperature
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DHEA

• Precursor of testosterone and estrogen.
• Elevated DHEA associated with protection function
  in aging diseases, diabetes, heart disease and
  cancer.
• Peak levels in humans occur at about 20 years of
  age in men and women.
• In 792 normal rhesus monkeys, DHEA levels dropped
  90 from infancy to 3 years followed by an
  average decline of 4.2 per yr

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DHEA steroid normally declines with age
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DHEA down 3 in CR males vs 30 for controls
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Reproduction

• Juveniles Reproductive maturation delayed in
  prepubescent monkeys on CR early in life.
• Adult males Testosterone level changes delayed
  by at least one year.
• Adult females Little difference in CR vs non-CR
  monkeys.

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Blood sugar, insulin

• CR monkeys able to regulate glucose better than
  controls.
• Lower fasting glucose and insulin levels after 3
  years.
• During intravenous glucose tolerance tests, max
  glucose level in CR less than in Control.
• Possible that CR increases insulin sensitivity
  and may postpone type II diabetes.

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• CR may alter basic mechanism of fuel use.
• Short term CR reduced fasting and peak insulin
  level prior to changes in adiposity.
• CR induced changes in lean (lt22 fat) monkeys.
• Suggests CR affects insulin levels independent of
  body weight and fat levels.

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Activity

• Monitored locomotor activity and basic behavior
  patterns in males after 6 yrs of CR.
• Used ultra-sonic motion detectors and video.
• Found daily activities and behaviors typical for
  captive primates.
• CR males displayed more pacing, gross movement
  and less passivity than control.
• CR female juveniles (6-8yrs) less active than
  control.

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Biomarkers of caloric restriction may predict
longevity in humans

• Roth, G. S., et al

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• Caloric restriction (CR) slows aging and
  maintains health and function in a diverse array
  of species ranging from worms and flies to
  rodents.

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• Rhesus monkey data showed that two
  highly-reproducible biomarkers of CR in rodents,
  reduced body temperature and reduced plasma
  insulin, also occur in CR rhesus monkeys.
• Serum DHEAS levels decline in aging monkeys and
  humans. CR also slows the rate of decline of
  DHEAS in CR monkeys.

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• Do body temperature, plasma insulin, and DHEAS
  predict human longevity?

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Methods

• The authors studied data from the Baltimore
  Longitudinal Study of Aging in Male Humans
  (BLSA).
• Obtained records of subjects body temperature,
  plasma insulin, and DHEAS,
• Divided the subjects into those in the upper half
  or those in the lower half of measurements of
  each biomarker.
• Compared survival of men in each group.

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Results

• Significant longer survival in men with lower
  body temperature, lower plasma insulin, and
  higher DHEAS (Figure 1) (p lt 0.05).
• The environmental or genetic factors that cause
  CR-like effects on body temperature, plasma
  insulin, and DHEAS in these men appear to be
  related to longevity.
• Suggest that the same mechanisms that control
  aging in animals are likely at work in humans,
  and that modifying these mechanisms may extend
  lifespan in humans.

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Demography of Dietary Restriction and Death in
Drosophila

• Mair, Goymer, Pletcher, Partridge

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• Mortality rate the probability of dying in any
  given interval, given the animal is alive at the
  start of the interval
• Hypothesis CR begun at any stage of life reduces
  the mortality rate to that of animals on lifetime
  CR

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Methods

• Four groups of flies
• CR for life
• Fully fed for life
• Fully fed, then switched to CR
• CR, then switched to fully fed

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Mortality in fully-fed switched to CR
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Mortality in CR to switched fully-fed
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Results

• Two days after starting CR for the first time,
  and at various ages, fully fed flies are no more
  likely to die than flies of the same age who have
  experienced long-term CR.
• Switching from CR to fully fed resulted in rapid
  increase of mortality levels. CR animals who
  switch to fully-fed have the same mortality rate
  as long-term fully fed flies.

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Conclusion

• It doesnt matter when CR is started. Switching
  to CR late in life reduces mortality to the same
  rate as long-term CR.

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Gene Expression Profiling of Aging Using DNA
Microarrays

• Weindruch, Kayo, Lee, Prolla

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DNA microarrays

• A tool that lets us measure biological age on a
  tissue specific basis.
• Allow evaluation of interventions at the
  molecular level.
• Allow study of 10,000 genes within a single
  experimental set-up.

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Gene expression in old vs young mouse (muscle
sample)
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Methods

• mice 30 months old housed individually
• fed non purified diet and acidified water AL for
  1week, then split into 2 groups
• Control mice fed 84kcal/week, about 20 less than
  standard diet
• necessary to avoid obesity and maintain motor
  activity
• CR mice fed 62kcal/week
• food enriched with protein, vitamins and minerals
  to match Control diet for nutrition

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Results

• 6347 genes surveyed
• 58 (0.9) displayed greater than 2-fold increase
  in gene expression
• 55 (0.9) displayed greater then 2-fold decrease
  in expression

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Gene groups affected

• Stress responses (including compensatory response
  to increased free radicals)
• Motor neuron genes
• Metabolism genes