Regulation of Aging and Lifespan

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Regulation of Aging and Lifespan
Old Age, Adolescence, Infancy Salvadore Dali
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Life Expectancy in US
28 years
1800
1900
47 years
70 years
2000
What is US world ranking in life expectancy?
24th
Who is 1?
Japan (74.5 years)
Life expectancey in Sierra Leone is 25.9 years
2000 Data from World Health Organization Report
on Life Expectancy
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Why do we die?

• Diseases and specific causes of death
• Accumulated cellular damage
• Lifespan is genetically programmed

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Diseases and Other Causes of Death

• Infectious disease pathogens and parasites
• Older peoples diseases
• Cancer, cardiovascular disease
• Were killing ourselves

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Why do we die?

• Diseases and specific causes of death
• Accumulated cellular damage
• Lifespan is genetically programmed

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The Oxygen Paradox Oxygen is essential for
aerobic respiration yet oxidative damage is toxic
and a likely cause of senescence
Reactive oxygen species (ROS) cause -Membrane
fatty acid peroxidation -Protein
modification/destruction -DNA damage
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Lifespan
Protein oxidation
control
Extra SOD and catalase
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The Oxygen Paradox Oxygen is essential for
aerobic respiration yet oxidative damage is toxic
and a likely cause of senescence
Reactive oxygen species (ROS) cause -Membrane
fatty acid peroxidation -Protein
modification/destruction -DNA damage
Metabolic Potential There is an inherent limit
to total amount of O2 consumed in a lifetime
-Decreased temperature extends lifespan in
cold-blooded animals -Flies that cant fly live
2.5 times longer
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Blocking Mitochondrial Function/Electron
Transport Chain Increases Lifespan
Obviously, these worms are not very happy
Dillin, 2002
Days of life
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Caloric Restriction Increases Lifespan
Also true for Flies, Worms and Yeast!
Mice
During times of limited nutrients, it may be
advantageious to switch metabolic resources from
reproduction to somatic maintenance
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The Cost of Reproduction
For many species and experimental situations,
Lifespan and Reproduction are inversely correlated
Does the metabolic cost of reproduction limit
lifespan?
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L1
Adult
Z2, Z3 germline Z1, Z4 somatic gonad
Germline ablation increases lifespan
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The Bad News You Cant Exercise, Eat or
Reproduce!
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BUT, Metabolic Potential Cant be the Whole Story
Cellular senescence is not inevitable The
Germline is immortal
Lifespans dont always fit metabolic potential
model e.g. Mice live 2-3 yrs Rats live 3
yrs Squirrels live 25 yrs Bats live 30-50 yrs
e.g. Honey Bees -Queen and worker have same
genotype -Worker lives few months -Queen lives
up to 5 years -Queen eats copiously and
constantly reproduces -Its Good to be the Queen!
Reproduction can be uncoupled from lifespan
Can select for long-lived stocks in flies and
lifespan mutants in different systems Therefore,
lifespan can be genetically programmed
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Why do we die?

• Diseases and specific causes of death
• Accumulated cellular damage
• Lifespan is genetically programmed

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Why would lifespan be genetically
programmed? -Increased reproductive life can
increase reproductive potential -Limiting
post-reproductive life could reduce competition
for resources between generations -Enhancing
post-reproductive life could increase survival of
future generations (grandmother effect)
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Yes, they really had 40 grandchildren in Quebec
in the 1800s
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Single Gene Mutations Can Dramatically Affect
Lifespan in C. elegans
daf-2 age-1
2-3 fold increase in lifespan (150-200 yrs old
for human)
daf-2, clk-1 double mutant 5-7 fold increase in
lifespan 500 years for human!!
daf-16 daf-18
Decrease lifespan
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Mutants in Dauer Formation Also Show Effects on
Lifespan
daf dauer formation defective Dauer larvae
alternate developmental stasis
stage -increased stress tolerance -increased
fat storage -decreased metabolism -decreased
reproduction Induced by starvation or other
high-stress conditions dauer phermone detected by
sensory system
Link between stress resistance and
longevity Stress may also increase lifespan
Stress is good!
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Lifespan Mutants are in the Insulin Signaling
Pathway
37 in C. elegans
Activation normally decreases lifespan
Signaling represses daf-16
DAF-16 normally represseslifespan
Increased Lifespan e.g. Superoxide dismutase
Nelson and Padgett, 2003
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Insulin Receptor Pathway Regulates Lifespan in
Flies and Mice
chico
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Nervous System Control Over Aging
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The Insulin Receptor Pathway is Required in the
Nervous System
All Neurons
All Cells
mutant
wt
transgene
Muscle
Intestine
Note other data indicates this pathway is also
important in the worm intestine and fly fat
body--both adipose tissues
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Could be that daf-2 pathway increases
stress/radical defenses and neurons are
particularly sensitive to this
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BUT, the Nervous System Can Also Negatively
Regulate Lifespan
Smelling or tasting food may be as detrimental to
lifespan as eating it!
Mutations affecting sensory neurons can increase
lifespan
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Many Insulin Like Peptides Are Expressed in
Nervous System
Daf-28 insulin peptide expressed in ASI and
ASJ Ablating ASI extends lifespan
Therefore, insulin receptor pathway required in
nervous system, but insulin signals also emanate
from nervous system
Pierce et al 2001 Li et al 2003 Alcedo 2004
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Environmental (Sensory) Cues
Increased Lifespan e.g. superoxide dismutase
protection from oxygen radicals
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Germline Control of Aging
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L1
Adult
Z2, Z3 germline Z1, Z4 somatic gonad
-Germline ablation increases lifespan -Blocking
gametogenesis does not - Ablation of both
germline and somatic gonad restores normal
lifespan -Therefore, increase in lifespan is not
directly due to reduced metabolic cost of not
reproducing -Lifespan is regulated by SIGNALS
from the germline through somatic gonad -Signal
appears dependent on germline stem cells
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The Germline Signals to Activate Daf-16 in the
Intestine
Germline ablation causes daf-16 nuclear
accumulation in adult intestine/adipose
tissue Animals with daf-16 expression only in
intestine respond normally to germline
ablation Therefore, germline signal likely acts
through daf-16 in intestine
Germline signal to daf-16 is INDEPENDENT of
insulin receptor and is DEPENDENT on nuclear
receptor daf-9
C. Kenyon and colleagues
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Environmental (Sensory) Cues
Increased Lifespan e.g. superoxide dismutase
protection from oxygen radicals
Germline Signal
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Studies of Aging in Yeast Uncover Role for Sir2
Sir2
(deacetylase)
Increased Lifespan
-Sir2 implicated in lifespan increase due to
caloric restriction in flies -Sir2 can regulate
lifepan in C. elegans (Dependent on
daf-16) -Sirt1 can regulate daf-16 acetylation
and activity in mice
Guarente and colleagues
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Resveratrol Polyphenol found in red
wine Activator of Sir2
Sir2
(deacetylase)
Increased Lifespan
Resveratrol causes increased lifespan in yeast
and caloric restriction has no additional effect
Howitz et al, Nature, 2003
The Good News We can DRINK RED WINE and eat
all we want!
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Environmental (Sensory) Cues
Reduced IGFs
Caloric Restriction
Sir2
Increased Lifespan e.g. superoxide dismutase
protection from oxygen radicals
Germline Signal
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Nutrition
Insulin From Nervous System
Germline Stem Cell Division and Oogenesis
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Environmental (Sensory) Cues
Reduced IGFs
Caloric Restriction
Sir2
Increased Lifespan e.g. superoxide dismutase
protection from oxygen radicals
Germline Signal
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Attempting to Integrate Metabolic vs. Genetic
Control of Aging
Nutrient Availability
Nervous System (Nutrients in Environment)
Fat Body/Intestine (Nutrients in Body)
Insulin Pathway
TOR Pathway
Sir2
Feedback about metabolism/reproduction
Longevity/Stress Resistance (Dauer) vs.
Active/Reproduction Mitochondrial Respiration Rate
Metabolic control of longevity may be more in a
signaling capacity than an absolute limit for
cellular/organismal physiology
Therefore, modulation of these pathways may allow
extension of lifespan without sacrificing quality
of life
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-4-phenylbutyrate, histone deacetylase
inhibitor (Sir2 is deacetylase, so unclear why
inhibiting deacetylases would extend
life) -Treated flies have normal fecudity and
movement -Treated flies are stress resistant
(more healthy!) -Previously FDA approved for
other uses