Limits on Human Lifespan and Molecular Effects on Ageing

1
Limits on Human Lifespan and Molecular Effects on
Ageing

• Leonid A. Gavrilov
• Natalia S. Gavrilova
• Center on Aging, NORC/University of Chicago,
• 1155 East 60th Street, Chicago, IL 60637

2
Questions of Scientific and Practical (Actuarial)
Significance

• How far could mortality decline go?
• (absolute zero seems implausible)
• Are there any biological limits to human
  mortality decline, determined by reliability of
  human body?
• (lower limits of mortality dependent on age,
  sex, and population genetics)
• Were there any indications for biological
  mortality limits in the past?
• Are there any indications for mortality limits
  now?

3
The Gompertz-Makeham Law

• µ(x) A R0exp(a x)
• A Makeham term or background mortality
• R0exp(a x) age-dependent mortality

4
Historical Changes in Mortality for 40-year-old
Swedish Males

• Total mortality
• Background mortality
• Age-dependent mortality
• Source Gavrilov, Gavrilova, The Biology of Life
  Span 1991

5
Historical Changes in Mortality for 40-year-old
Women in Norway and Denmark

• Norway, total mortality
• Denmark, total mortality
• Norway, age-dependent mortality
• Denmark, age-dependent mortality
• Source Gavrilov, Gavrilova, The Biology of Life
  Span 1991

6
Historical Changes in Mortality for 40-year-old
Italian Women and Men

• Women, total mortality
• Men, total mortality
• Women, age-dependent mortality
• Men, age-dependent mortality
• Source Gavrilov, Gavrilova, The Biology of Life
  Span 1991

7
Historical Changes in Mortality Swedish Females
8
Historical Changes in Survival from Age 90 to 100
years. France
9
Historical Changes in Survival from Age 90 to 100
years. Japan
10
Extension of the Gompertz-Makeham Model through
the Factor Analysis of Mortality Trends

• Mortality force (age, time)
• a0(age) a1(age) x F1(time) a2(age) x
  F2(time)

11
Factor Analysis of Mortality Swedish Females
12
Preliminary Conclusions

• There was some evidence for biological
  mortality limits in the past, but these limits
  proved to be responsive to the recent
  technological and medical progress.
• Thus, there is no convincing evidence for
  absolute biological mortality limits now.
• Analogy for illustration and clarification There
  was a limit to the speed of airplane flight in
  the past (sound barrier), but it was overcome
  by further technological progress. Similar
  observations seems to be applicable to current
  human mortality decline.

13
Molecular Effects on Ageing

• New Ideas and Findings by Bruce Ames
• The rate of mutation damage is NOT immutable, but
  it can be dramatically decreased by very simple
  measures
• -- Through elimination of deficiencies in
  vitamins and other micronutrients (iron, zinc,
  magnesium, etc).
• Micronutrient deficiencies are very common even
  in the modern wealthy populations
• These deficiencies are much more important than
  radiation, industrial pollution and most other
  hazards

Our hypothesis Remarkable improvement in the
oldest-old survival may reflect an unintended
retardation of the aging process, caused by
decreased damage accumulation, because of
improving the micronutrient status in recent
decades
14
Micronutrient Undernutrition in Americans
lt50 RDA
ingesting lt RDA
Population Group
Nutrient
ingesting lt 50 RDA
RDA
Minerals
25
75
18 mg
Women 20-30 years
Iron
5-10
25
8 mg
Women 50 years

Men Women 50 years
11 8 mg
50
10
Zinc
Vitamins
10
50
1.7 1.5 mg
Men Women
B6
75
25 50
400 mcg
Men Women
Folate
5 10-25
10-20 25-50
2.4 mcg
Men Women
B12
50
90 75 mg
Men Women
C
25
Wakimoto and Block (2001) J Gerontol A Biol Sci
Med Sci. Oct 56 Spec No 2(2)65-80. Before
U.S. Food Fortification Source
Presentation by Bruce Ames at the IABG Congress
15
Molecular Effects on Ageing (2)

• Ideas and Findings by Bruce Ames
• The rate of damage accumulation is NOT immutable,
  but it can be dramatically decreased by
  PREVENTING INFLAMMATION
• Inflammation causes tissue damage through many
  mechanisms including production of Hypochlorous
  acid (HOCl), which produces DNA damage (through
  incorporation of chlorinated nucleosides).
• Chronic inflammation may contribute to many
  age-related degenerative diseases including cancer

Hypothesis Remarkable improvement in the
oldest-old survival may reflect an unintended
retardation of the aging process, caused by
decreased damage accumulation, because of partial
PREVENTION of INFLAMMATION through better control
over infectious diseases in recent decades
16
Characteristic of our Dataset

• Over 16,000 persons belonging to the European
  aristocracy
• 1800-1880 extinct birth cohorts
• Adult persons aged 30
• Data extracted from the professional genealogical
  data sources including Genealogisches Handbook
  des Adels, Almanac de Gotha, Burke Peerage and
  Baronetage.

17
Season of Birth and Female Lifespan8,284 females
from European aristocratic families born
in 1800-1880Seasonal Differences in Adult
Lifespan at Age 30

• Life expectancy of adult women (30) as a
  function of month of birth (expressed as a
  difference from the reference level for those
  born in February).
• The data are point estimates (with standard
  errors) of the differential intercept
  coefficients adjusted for other explanatory
  variables using multivariate regression with
  categorized nominal variables.

18
Season of Birth and Female Lifespan6,517 females
from European aristocratic families born
in 1800-1880Seasonal Differences in Adult
Lifespan at Age 60

• Life expectancy of adult women (60) as a
  function of month of birth (expressed as a
  difference from the reference level for those
  born in February).
• The data are point estimates (with standard
  errors) of the differential intercept
  coefficients adjusted for other explanatory
  variables using multivariate regression with
  categorized nominal variables.

19
Mean Lifespan of FemalesBorn in December and
Februaryas a Function of Birth Year

• Life expectancy of adult women (30) as a
  function of year of birth

20
Daughters' Lifespan (30) as a Functionof
Paternal Age at Daughter's Birth6,032 daughters
from European aristocratic familiesborn in
1800-1880

• Life expectancy of adult women (30) as a
  function of father's age when these women were
  born (expressed as a difference from the
  reference level for those born to fathers of
  40-44 years).
• The data are point estimates (with standard
  errors) of the differential intercept
  coefficients adjusted for other explanatory
  variables using multiple regression with nominal
  variables.
• Daughters of parents who survived to 50
  years.

21
Daughters' Lifespan (60) as a Functionof
Paternal Age at Daughter's Birth4,832 daughters
from European aristocratic familiesborn in
1800-1880

• Life expectancy of older women (60) as a
  function of father's age when these women were
  born (expressed as a difference from the
  reference level for those born to fathers of
  40-44 years).
• The data are point estimates (with standard
  errors) of the differential intercept
  coefficients adjusted for other explanatory
  variables using multiple regression with nominal
  variables.
• Daughters of parents who survived to 50
  years.

22
Paternal Age as a Risk Factor for Alzheimer
Disease

• MGAD - major gene for Alzheimer Disease
• Source L. Bertram et al. Neurogenetics, 1998, 1
  277-280.

23
Paternal Age and Risk of Schizophrenia

• Estimated cumulative incidence and percentage of
  offspring estimated to have an onset of
  schizophrenia by age 34 years, for categories of
  paternal age. The numbers above the bars show the
  proportion of offspring who were estimated to
  have an onset of schizophrenia by 34 years of
  age.
• Source Malaspina et al., Arch Gen
  Psychiatry.2001.

24
Aging is a Very General Phenomenon!
25
What Should the Aging Theory Explain

• Why do most biological species deteriorate with
  age?
• Specifically, why do mortality rates increase
  exponentially with age in many adult species
  (Gompertz law)?
• Why does the age-related increase in mortality
  rates vanish at older ages (mortality
  deceleration)?
• How do we explain the so-called compensation law
  of mortality (Gavrilov Gavrilova, 1991)?

26
Exponential Increase of Death Rate with Age in
Fruit Flies(Gompertz Law of Mortality)

• Linear dependence of the logarithm of
  mortality force on the age of Drosophila.
• Based on the life table for 2400 females
  of Drosophila melanogaster published by Hall
  (1969). Mortality force was calculated for
  3-day age intervals.
• Source Gavrilov, Gavrilova,
• The Biology of Life Span 1991

27
Age-Trajectory of Mortality in Flour
Beetles(Gompertz-Makeham Law of Mortality)

• Dependence of the logarithm of mortality
  force (1) and logarithm of increment of mortality
  force (2) on the age of flour beetles (Tribolium
  confusum Duval).
• Based on the life table for 400 female
  flour beetles published by Pearl and Miner
  (1941). Mortality force was calculated for
  30-day age intervals.
• Source Gavrilov, Gavrilova, The Biology of Life
  Span 1991

28
Age-Trajectory of Mortality in Italian
Women(Gompertz-Makeham Law of Mortality)

• Dependence of the logarithm of
  mortality force (1) and logarithm of increment of
  mortality force (2) on the age of Italian women.
• Based on the official Italian period
  life table for 1964-1967. Mortality force was
  calculated for 1-year age intervals.
• Source Gavrilov, Gavrilova,
• The Biology of Life Span 1991

29
Compensation Law of MortalityConvergence of
Mortality Rates with Age

• 1 India, 1941-1950, males
• 2 Turkey, 1950-1951, males
• 3 Kenya, 1969, males
• 4 - Northern Ireland, 1950-1952, males
• 5 - England and Wales, 1930-1932, females
• 6 - Austria, 1959-1961, females
• 7 - Norway, 1956-1960, females
• Source Gavrilov, Gavrilova,
• The Biology of Life Span 1991

30
Compensation Law of Mortality in Laboratory
Drosophila

• 1 drosophila of the Old Falmouth, New Falmouth,
  Sepia and Eagle Point strains (1,000 virgin
  females)
• 2 drosophila of the Canton-S strain (1,200
  males)
• 3 drosophila of the Canton-S strain (1,200
  females)
• 4 - drosophila of the Canton-S strain (2,400
  virgin females)
• Mortality force was calculated for 6-day age
  intervals.
• Source Gavrilov, Gavrilova,
• The Biology of Life Span 1991

31
Mortality at Advanced Ages

• Source Gavrilov L.A., Gavrilova N.S. The
  Biology of Life Span
• A Quantitative Approach, NY Harwood Academic
  Publisher, 1991

32
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33
M. Greenwood, J. O. Irwin. BIOSTATISTICS OF
SENILITY
34
Survival Patterns After Age 90

• Percent surviving (in log scale) is
  plotted as a function of age of Swedish women for
  calendar years 1900, 1980, and 1999
  (cross-sectional data). Note that after age 100,
  the logarithm of survival fraction is decreasing
  without much further acceleration (aging) in
  almost a linear fashion. Also note an increasing
  pace of survival improvement in history it took
  less than 20 years (from year 1980 to year 1999)
  to repeat essentially the same survival
  improvement that initially took 80 years (from
  year 1900 to year 1980).
• Source cross-sectional (period) life
  tables at the Berkeley Mortality Database (BMD)
• http//www.demog.berkeley.edu/bmd/

35
Non-Gompertzian Mortality Kinetics of Four
Invertebrate Species

• Non-Gompertzian mortality kinetics of four
  invertebrate species nematodes, Campanularia
  flexuosa, rotifers and shrimp.
• Source A. Economos. A
  non-Gompertzian paradigm for mortality kinetics
  of metazoan animals and failure kinetics of
  manufactured products. AGE, 1979, 2 74-76.

36
Non-Gompertzian Mortality Kinetics of Three
Rodent Species

• Non-Gompertzian mortality kinetics of three
  rodent species guinea pigs, rats and mice.
• Source A. Economos. A non-Gompertzian
  paradigm for mortality kinetics of metazoan
  animals and failure kinetics of manufactured
  products. AGE, 1979, 2 74-76.

37
Non-Gompertzian Mortality Kinetics of Three
Industrial Materials

• Non-Gompertzian mortality kinetics of three
  industrial materials steel, industrial relays
  and motor heat insulators.
• Source A. Economos. A non-Gompertzian
  paradigm for mortality kinetics of metazoan
  animals and failure kinetics of manufactured
  products. AGE, 1979, 2 74-76.

38
Redundancy Creates Both Damage Tolerance and
Damage Accumulation (Aging)
39
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40
Differences in reliability structure between (a)
technical devices and (b) biological systems
41
Statement of the HIDL hypothesis(Idea of High
Initial Damage Load )

• "Adult organisms already have an exceptionally
  high load of initial damage, which is comparable
  with the amount of subsequent aging-related
  deterioration, accumulated during the rest of the
  entire adult life."

Source Gavrilov, L.A. Gavrilova, N.S. 1991.
The Biology of Life Span A Quantitative
Approach. Harwood Academic Publisher, New York.
42
Why should we expect high initial damage load ?

• General argument--  In contrast to technical
  devices, which are built from pre-tested
  high-quality components, biological systems are
  formed by self-assembly without helpful external
  quality control.
• Specific arguments

1. Cell cycle checkpoints are disabled in early
   development     (Handyside, Delhanty,1997. Trends
   Genet. 13, 270-275 )
2. extensive copy-errors in DNA, because most cell
   divisions   responsible for  DNA copy-errors
   occur in early-life   (loss of telomeres is also
   particularly high in early-life)
3. ischemia-reperfusion injury and
   asphyxia-reventilation injury   during traumatic
   process of 'normal' birth

43
Spontaneous mutant frequencies with age in heart
and small intestine
Source Presentation of Jan Vijg at the IABG
Congress, Cambridge, 2003
44
Birth Process is a Potential Source of High
Initial Damage

• During birth, the future child is deprived of
  oxygen by compression of the umbilical cord and
  suffers severe hypoxia and asphyxia. Then, just
  after birth, a newborn child is exposed to
  oxidative stress because of acute reoxygenation
  while starting to breathe. It is known that
  acute reoxygenation after hypoxia may produce
  extensive oxidative damage through the same
  mechanisms that produce ischemia-reperfusion
  injury and the related phenomenon,
  asphyxia-reventilation injury. Asphyxia is a
  common occurrence in the perinatal period, and
  asphyxial brain injury is the most common
  neurologic abnormality in the neonatal period
  that may manifest in neurologic disorders in
  later life.

45
Practical implications from the HIDL hypothesis

• "Even a small progress in optimizing the
  early-developmental processes can potentially
  result in a remarkable prevention of many
  diseases in later life, postponement of
  aging-related morbidity and mortality, and
  significant extension of healthy lifespan."
• "Thus, the idea of early-life programming of
  aging and longevity may have important practical
  implications for developing early-life
  interventions promoting health and longevity."

Source Gavrilov, L.A. Gavrilova, N.S. 1991.
The Biology of Life Span A Quantitative
Approach. Harwood Academic Publisher, New York.
46
Failure Kinetics in Mixtures of Systems with
Different Redundancy LevelsInitial Period

• The dependence of logarithm of mortality
  force (failure rate) as a function of age in
  mixtures of parallel redundant systems having
  Poisson distribution by initial numbers of
  functional elements (mean number of elements, ?
  1, 5, 10, 15, and 20.

47
Daughter's Lifespan(Mean Deviation from Cohort
Life Expectancy)as a Function of Paternal
Lifespan

• Offspring data for adult lifespan (30 years) are
  smoothed by 5-year running average.
• Extinct birth cohorts (born in 1800-1880)
• European aristocratic families. 6,443
  cases

48
Offspring Lifespan at Age 30 as a Function
of Paternal LifespanData are adjusted for
other predictor variables
Daughters, 8,284 cases
Sons, 8,322 cases
49
Offspring Lifespan at Age 60 as a Function
of Paternal LifespanData are adjusted for
other predictor variables
Daughters, 6,517 cases
Sons, 5,419 cases
50
Offspring Lifespan at Age 30 as a Function
of Maternal LifespanData are adjusted for
other predictor variables
Daughters, 8,284 cases
Sons, 8,322 cases
51
Offspring Lifespan at Age 60 as a Function
of Maternal LifespanData are adjusted for
other predictor variables
Daughters, 6,517 cases
Sons, 5,419 cases
52
Persons Lifespan as a Function of Spouse
LifespanData are adjusted for other predictor
variables
Married Women, 6,442 cases
Married Men, 6,596 cases
53
Conclusions (I)

• Redundancy is a key notion for understanding
  aging and the systemic nature of aging in
  particular. Systems, which are redundant in
  numbers of irreplaceable elements, do deteriorate
  (i.e., age) over time, even if they are built of
  non-aging elements.
• An actuarial aging rate or expression of aging
  (measured as age differences in failure rates,
  including death rates) is higher for systems with
  higher redundancy levels.

54
Conclusions (II)

• Redundancy exhaustion over the life course
  explains the observed compensation law of
  mortality (mortality convergence at later life)
  as well as the observed late-life mortality
  deceleration, leveling-off, and mortality
  plateaus.
• Living organisms seem to be formed with a high
  load of initial damage, and therefore their
  lifespans and aging patterns may be sensitive to
  early-life conditions that determine this initial
  damage load during early development. The idea of
  early-life programming of aging and longevity may
  have important practical implications for
  developing early-life interventions promoting
  health and longevity.

55
Acknowledgments

• This study was made possible thanks to
• generous support from the National Institute on
  Aging, and
• stimulating working environment at the Center
  on Aging, NORC/University of Chicago