Systems Biology of Human Aging:

1
Andrus Gerontology Ctr, Dept Biological Sciences
Caleb E Finch
Systems Biology of Human Aging An ecological
perspective on the roles of inflammation and
nutrition
2
The Gero-Inflammatory Manifold
External Environment
Internal environment
nutrition therapeutic drugs infections inflammo
gens air pollution toxins stress
physical social positive social
interactions
3
Chronic inflammatory processes are ubiquitous
during adult aging

• progressive postnatal changes
• monocyte activation artery, brain, lung,
• oxidatively damaged elastin and matrix proteins
  that attract monocytes
• later ages
• increased blood CRP and IL-6
• increased proinflammatory gene expression in most
  tissues
• T cell senescence

4
Long-lived proteins accumulate damage
1. oxidative damage during normal metabolism
from free radicals and glyco-oxidation
Paradox oxygen glucose are essential for life,
but cause random damage to DNA and proteins 2.
oxidative damage from tissue inflammation-
importance of macrophages 3.Macrophages attack
invaders with free radicals and cause by-stander
damage
5
Molecular and cell aging
Lifespans of molecules and cells
determined during development by patterns of
gene expression for each cell type
Transcription factors lock-in or lock-out
gene activity for cell and molecular and cell
replacement e.g. elastin and stem cells
6
aorta - aging of irreplaceable elastindamage
from glucose and inflammationFornieri C,
Arterioscler Thromb 1992 Finch CE, 2007, p.17
young rat
glyco-oxidized elastin

racemized elastin
old rat elastin fragmentation with local
macrophages
human age
7
Shared inflammatory processes in normal aging and
diseasesactive macrophages/monocyteslocal
oxidative damage from free radicals
arterial Alzheimer
senile atheroma plaque
J-O Daguchi Circ 2006
CJ Pike, pers comm
8
Arterial lesions are active at birth
Oil-red positive areas Age
25, intimal thickness (DArmiento et al Stroke
2001) (Homa S,
Atherosclerosis, 2001)
smoking, air pollution
aorta coronary
??
9
Shared inflammatory mechanismsin atherosclerosis
and Alzheimer disease?
CE Finch, Neurobiol Aging, 2005
10
Chronic infection and inflammationincrease risk
of

• Arterial disease
• Alzheimer disease
• Some cancers
• (GI tract, Helicobacter pylori)

11
Hypothesis diet and inflammationare major
factors in the human lifespan by influencing the
progression of atherosclerosis, cancer, and
Alzheimer disease
12
interactions of oxidative stress and inflammmation

• bystander damage from oxidative stress stimulates
  inflammatory processes
• inflammation causes bystander damage
• Nutritional influences on bystander damage

13
Diet restriction attenuates amyloid deposits
-35 ad lib/ 4 mo familial Alzheimer transgenic
miceNV Patel et al, Neurobiol Aging, 2005
14
Caloric restriction of lab rodents slows most
aspects of aging

• Slows mortality acceleration rate constant
  (Gompertz slope)
• attenuates strain specific organ degeneration
• Attenuates systemic and tissue oxidative damage
• Attenuates inflammatory gene expression
• Impairs wound healing and some adaptive immune
  responses

15
Anti-inflammatory drugs statins protect
against many chronic diseases of aging

• Cardiovascular (aspirin, statins) -30-50
• Cancer -30-50
• colo-rectal (NSAIDs)
• esophageal (NSAIDs )
• breast (aspirin)?
• 3. Alzheimer disease
• (NSAIDs, aspirin, statins)?

16
Ibuprofen in ad lib diet attenuates brain
amyloid deposits APPswe/ind familial AD mouse
TE Morgan CE Finch 2004
(375 ppm 4 mo)
17
Coronary risks associate with the of different
infections (seropositivities, CMV, EBV, HSV1 ,C
Pneumoniae, H Pylori, H influenzae) Zhu et al Am
J Cardiol 2000
18
AIDS induces brain amyloidAbeta- containing
diffuse plaques in frontal cortex Rempel HC
AIDS 19 127 2005
AIDS AD
Tat protein of HIV inhibits enzymatic degradation
of A? (neprolysin)
2 y 18y
19
Long-term air pollution exposure accelerates
markers of brain aging young adults Mexico City
vs VeracruzCalduron-Garciduenas et al Toxicol
Pathol 2008

• disrupted blood-brain barrier
• ultrafine carbon particles in brain olfactory
  neurons
• 8-OHG in neurons
• activated microglia and astrocytes in cerebral
  cortex NFkB, COX-2 induction
• accumulated amyloid ß-42/?-synuclein

20
Diffuse amyloid Aß42 deposits in brains of
Mexico City (MxC) vs control city(CTL) young
adults E3, apoE3 E4, apoE4
Calduron-Garciduenas et al Toxicol Pathol 2008
21
Aging increases IL-6in mixed gliaXie et al,
Exp Neurol 2003
Ratio of Old/Young
22
neuron stem cell survivalin primary culture is
lower with aging astrocytes
Young astrocytes
young astrocytes old astrocytes
Old astrocytes
GFAP, orange MAP2, green.
Rozovsky, Morgan, Finch, in prep.
23
dopaminergic neuron grafts less outgrowth in
aging rats (Collier et al., J Neurosci, 1999).
Ventral mesencephalic grafts in rats of varying
age and lesion duration. Tyrosine hydroxylase
staining for dopaminergic neurons 10 weeks after
grafting into rats given 6-OHDA lesions at age 3
mo to destroy dopamine neurons. STY, short-term
lesioned young (4 mo) LTM, long-term lesioned
middle-age (12 mo) LTO, long-term lesioned old
(24 mo).
24
Historical increases of life expectancyOepen and
Vaupel, Science 2002 C Finch adaptation
Phase 1 Phase 2 Phase 3? early
urban sanitation-nutrition
regeneration
modern medicine
?
25
Walt Whitman at 45 I am in good spirits
only getting old - most 50, you know.(letter,
Feb 12, 1867)
26
Hypothesis of historical increase in lifespan,
1750 to presentFinch Crimmins, Science 2004,
PNAS 2006

• aging has slowed
• Improved diet and hygiene decreased infections
  1750-1900
• decreased infection and inflammation slowed aging
• vaccination (1890) antibiotics (1950)

27
Infant mortality heart diseasein Norway by
cohort 40-69 yr latersurvivors in cohorts with
high infant mortality carry life-long
vulnerability Forsdahl A Brit J Prevt Social
Med 31 91-95 1977
28
Mortality in Sweden 1751-1940birth cohort vs
historical period Finch Crimmins, Science
2004, 2005 PNAS 2006
29
Cohort mortality in Sweden 1751-1940 cohort
morbidity phenotypesame slope but different
interceptsdemographic aging is increasingly
delayed
30
Inflammatory hypothesis of the historical
increase of human life spans

• strong correlations between early and later age
  mortality in cohorts
• survivors of infections carry inflammatory loads,
  even if infections are latent or cured
• slower development of the chronic conditions of
  old age

31
Adult height increased inversely with infant
mortality in 19th C Sweden and FranceCrimmins
and Finch PNAS 2006

32
Resource allocation
Healthy infected
??ergonomics of gene regulatory systems??
33
Minimum mortality qmin calculation of potential
lifespan

• Minimum mortality qmin the lowest mortality
  rates are observed at puberty
• portion of the mortality curve between the
  descending early mortality and ascending
  mortality acceleration associated with senescence
  (Gompertz curve).
• levels and duration of qmin indicate the onset
  of senescence (Gompertz acceleration)
• qmin may estimate lifespans in the absence of
  senescence

34
qmin chimps vs hunter-gatherers
Minimum mortality rate qmin
Mortality Rate/yr 1.0 0.1 0.01
0.001
Survival
H
C
C
H
35
qmin, cohorts, 4 Countries, 1751-1989
antibiotics ?
36
Hypothetical lifespan in absence of aging with
constant qmin

• If subadult qmin were maintained indefinitely,
  survival curves would be described by
• 0th order kinetics, like radioactive decay
• N/No exp(qmin)time
• Median lifespan half-life or ln2/qmin
• Sweden 1751, qmin 0.006 median ,115 y
• Sweden 1998, qmin 0.000 03 median 23,000 y

37
1985 Obesity
Mokdad A H, et al. J Am Med Assoc28216,
1999,28610 2001.
38
1995 Obesity
39
2001 Obesity
40
Russian longevity crash- will other nations
follow?
Britain

14 y
3 y
Russia
41
Opposing changes in the future of longevity

• Pro-longevity
• stem cells and regenerative medicine
• new drugs genetic risk profiles
• Anti-longevity
• obesity epidemic
• growing air pollution inflammogens (fossil
  fuels dust from deforestation)
• more infections
• (increased crowding decreased sanitation and
  clean water)
• spread by global commerce travel

42
determinants of individual aging

• I, inherited genetic differences
• II, random cell variations during development
• III, somatic cell DNA damage during aging
• IV, somatic cell damage from environment
  infection, inflammation, pollution, nutrition,
  stress
• III-IV random hits during aging create individual
  mosaics of diverse tissue differences
• potential interventions
• diet-drugs to slow inflammation and oxidative
  damage
• regenerative medicine at level of gene regulation
  for control of molecular lifespan and cell
  regeneration

43
We dont know the future ofthe human life span
Gustav Vigeland, Oslo
44
Synaptic changes are concurrent with progressive
increases of astrocytic volume and GFAP
expression during normal aging, in absence of
amyloid accumulation (rodent) or in absence
Alzheimer disease (human).Hypothesis age
increase of GFAP as a factor in synaptic
regression during aging
45
E18 neurite outgrowth in heterochronic cultures
of astrocytes young (3 mo) gt old (24 mo)
Rozovsky et al. Neurobiol Aging 2005
young old
46
age impairment of neurite outgrowth reversed
bySiRNA diminution of GFAP in old astrocytes
47
Atheromas are hotIn vivo thermography of
atherosclerotic plaquesA, control rabbitB,
cholesterol-fed 3 mo atheroma1oCC. 3 mo return
dietVerheye S Circulation 2002
48
Chronic diseases of agingbegin early

• Fetal arteries microscopic atheromas
• Atherosclerosis accelerated by environment
• Mild brain inflammation and
• neuronal atrophy by age 50
• extreme development in Alzheimers
• environmental effects in Alz implied

49
Biochemistry of aging

• free radicals cause oxidative damage
• unpaired electron chemically oxidizes and
  combines with proteins, lipids, DNA (mutations)
• superoxide, hydrogen peroxide, nitric
  oxide
• Glucose causes oxidative damage (glyco-oxidation)
• spontaneous reaction that chemically oxidizes
  and combines with proteins, lipids, DNA