Diapositiva 1

1
How we age according to Programmed Aging
Paradigm  Giacinto Libertini giacinto.libertini_at_t
in.it www.r-site.org/ageing  
www.programmed-aging.org Proposed to
International Association of Gerontology and
Geriatrics European Region (IAGG-ER) 8th Congress
23-26 April 2015, Dublin, Ireland
2
There are two antithetical general explanations
for aging 1, here precisely defined as
age-related progressive fitness decline or
mortality increase. They are totally different
and have very important opposed implications.
Therefore, they deserve to be defined
paradigms.
The first, here defined as the Old Paradigm,
explains aging as the effect of various factors
insufficiently opposed by natural selection 2
Aging is the main FAILURE of evolution!
The second, here defined as the New Paradigm,
explains aging as a physiologic phenomenon
determined and favored by supra-individual
selection in particular conditions 3 Aging is
an extraordinary ACHIEVEMENT of evolution!
The two paradigms, by definition, are
incompatible with each other.
1 Goldsmith T. The Evolution of Aging (3rd
ed.). Azinet Press, USA 2013. 2 Kirkwood TBL
Austad SN. Why do we age? Nature 2000
408233-8. 3 Libertini G. Empirical evidence
for various evolutionary hypotheses on species
demonstrating increasing mortality with
increasing chronological age in the wild.
TheScientificWorld Journal 2008 8183-93.
3
For the New Paradigm, aging is a particular type
of phenoptosis
The concept of phenoptosis 1, 2 includes a
large category of well-known phenomena 3
characterized by the self-sacrifice of an
individual (genetically caused / induced and
regulated, favored by natural selection, in
terms of supra-individual selection).
Etc.
Autogeny
Aphagy in adult insects
Aging (slow phenoptosis 4)
Death after spawning
Hormonally triggered senescence in plants
Death of the male associated with mating /
reproduction
Endotokic matricide
1 Skulachev VP. Aging is a specific biological
function rather than the result of a disorder in
complex living systems biochemical evidence in
support of Weismann's hypothesis. Biochem (Mosc)
1997 62(11)1191-5. 2 Libertini G.
Classification of Phenoptotic Phenomena. Biochem
(Mosc) 2012 77(7)707-15. 3 Finch CE.
Longevity, Senescence and the Genome, University
of Chicago Press, London 1990. 4 Skulachev VP.
Programmed Death Phenomena From Organelle to
Organism. Ann NY Acad Sci 2002 959214-37.
4
Here, I do not want to discuss arguments and
evidence for or against the two paradigms, but
only focus on a key topic how we age, i.e. a
general description of aging process in our
species (and in mammals in general) on the basis
of mechanisms genetically determined and
regulated.
The New Paradigm predicts and requires the
existence of specific mechanisms, genetically
determined and regulated, which cause aging 1.
On the contrary, the Old Paradigm excludes the
possibility that such mechanisms exist their
existence would therefore demonstrate that the
paradigm is false 2.
Only clear and accepted evidence will be used in
the following exposition.
1 Libertini G. Empirical evidence for various
evolutionary hypotheses on species demonstrating
increasing mortality with increasing
chronological age in the wild, TheScientificWorld
Journal 2008 8183-93. 2 Kirkwood TBL, Austad
SN. Why do we age? Nature 2000 408233-8.
5
First evidence Programmed Cell Death (PCD)

• A cell may dies by necrosis because of accidental
  events (injury, mechanical stress, infection,
  ischemia, etc.), or by one of various types of
  PCD, e.g.
• - The keratinization of epidermis or hair cells
• - The detachment of cells from the lining of
  intestines or other body cavities
• Osteocytes phagocytized by osteoclasts
• The transformation of erythroblasts in
  erythrocytes and their subsequent removal by
  macrophages.
• Apoptosis, an ordinate process of
  self-destruction with non-damaging disposal of
  cellular debris that makes it different from
  necrosis. The phenomenon was for the first time
  described and clearly differentiated from
  necrosis in the observation of normal hepatocytes
  1. A pivotal function of apoptosis in
  vertebrates is related to cell turnover in
  healthy adult organs, as well documented for many
  tissues and organs 2.

Beware PCD is often used as synonymous of
apoptosis, but this is a wrong simplification!
1 Kerr JFR et al. Apoptosis a basic biological
phenomenon with wide-ranging implications in
tissue kinetics. Br. J. Cancer 1972
26239-57. 2 Libertini G. The Role of
Telomere-Telomerase System in Age-Related Fitness
Decline, a Tameable Process, in Telomeres
Function, Shortening and Lengthening, Nova Sc.
Publ., New York, 2009.
6
Second evidence Cell Turnover
The continuous death of cells by PCD is balanced
by an equal proliferation of appropriate stem
cells, which is regulated and limited by
telomere-telomerase system. Each day,
approximately 50 to 70 billion cells perish in
the average adult because of programmed cell
death (PCD). Cell death in self-renewing tissues,
such as the skin, gut, and bone marrow, is
necessary to make room for the billions of new
cells produced daily. So massive is the flux of
cells through our bodies that, in a typical year,
each of us will produce and, in parallel,
eradicate, a mass of cells equal to almost our
entire body weight 1.
1 Reed JC. Dysregulation of Apoptosis in
Cancer. J Clin Oncol 1999 172941-53.
Cell death by PCD
CELL TURNOVER
Duplication of stem cells
Cell turnover is a general pattern in
vertebrates, but not for all animals (e.g., the
adult stage of the worm Caenorhabditis elegans
has a fixed number of cells).
7
Cell Turnover (continued)
The rhythm of cell turnover varies greatly
depending on cell type and organ. In the
intestinal epithelium cells are replaced every
three to six days, while Bone has a turnover
time of about ten years in humans 1.
VERY SLOW
SLOW
VERY QUICK
QUICK
1 Alberts B. et al. Essential Cell Biology, 4
ed., Garland Science, 2013.
8
Third evidence on/off cell senescence and
gradual cell senescence
Cell replication, which is essential to allow
cell turnover, is limited by known mechanisms. In
1961, Hayflick demonstrated that cells divide
only a finite number of times 1. Olovnikov
hypothesised that, as DNA molecule shortens at
each duplication, this could explain the finite
number of duplications 2. The end of DNA
molecule (telomere) was shown, first in a
protozoan species, to be a simple repeated
sequence of nucleotides 3. The discovery of
telomerase which added other sequences of the
nucleotides was a necessary explanation for
cells, as those of germ line, capable of
numberless divisions 4. Telomerase was shown to
be repressed by regulatory proteins 5. In cells
where telomerase is not active, an infinite
number of duplications is impossible for the
progressive telomere shortening. Before telomeres
reach their minimum length, two phenomena are
described ...
1 Hayflick L Moorhead PS. The serial
cultivation of human diploid cell strains. Exp
Cell Res 1961 25585-621. 2 Olovnikov AM. A
theory of marginotomy The incomplete copying of
template margin in enzyme synthesis of
polynucleotides and biological significance of
the problem. J Theor Biol 1973 41181-90. 3
Blackburn EH Gall JG. A tandemly repeated
sequence at the termini of the extrachromosomal
ribosomal RNA genes in Tetrahymena. J Mol Biol
1978 12033-53. 4 Greider CW Blackburn EH.
Identification of a specific telomere terminal
transferase activity in Tetrahymena extracts.
Cell 1985 51405-13. 5 van Steensel B de
Lange T. Control of telomere length by the human
telomeric protein TRF1. Nature 1997 385740-3.
9

1. on/off cell senescence

In a cell in cycling state, the telomere,
whatever its length, oscillates between two
phases capped and uncapped (by a protein
complex). The probability of the uncapped phase
is inversely proportional to the relative
reduction of telomere length. In the uncapped
phase, the cell is vulnerable to the transition
to non-cycling state, i.e. to the activation of
cell senescence program 1.
Figure 1 from 1
1 Blackburn EH. Telomere states and cell fates.
Nature 2000 40853-6.
10

1. on/off cell senescence (continued)

Cell senescence, which can also be activated by
other factors, is determined by a mechanism in
which the p53 protein is involved. It is
characterized by the block of the cell cycle and
by a long series of changes in the expression of
cellular genes. These changes also include
alterations of cellular secretions that cause
alterations of the extracellular matrix,
inflammation, reduced secretion of important
structural proteins such as elastin and collage,
and impairments of the surrounding cells 1. The
alterations are stereotyped and predictable cell
senescence has been described as a fundamental
cellular program 2.
1 Fossel MB. Cells, Aging and Human Disease.
Oxford University Press, New York 2004. 2
Ben-Porath I Weinberg R. The signals and
pathways activating cellular senescence. Int J
Biochem Cell Biol 2005 3796176.
11
2) gradual cell senescence
The progressive shortening of telomeres has
another effect. The telomere is covered (capped)
by a protein complex that, as the telomere
shortens, hides the subtelomeric DNA and causes
transcriptional silencing. As the telomere
shortens, the hood slides further down the
chromosome .... the result is an alteration of
transcription from
Figure 7 from 2
portions of the chromosome immediately adjacent
to the telomeric complex, usually causing
transcriptional silencing, although the control
is doubtless more complex than merely telomere
effect through propinquity These silenced genes
may in turn modulate other, more distant genes
(or set of genes). There is some direct evidence
for such modulation in the subtelomere ... 1
1 Fossel MB. Cells, Aging and Human Disease.
Oxford University Press, New York 2004. 2
Libertini G. The Role of Telomere-Telomerase
System in Age-Related Fitness Decline, a Tameable
Process, in Telomeres Function, Shortening and
Lengthening, Nova Sc. Publ., New York 2009.
12
on/off cell senescence and gradual cell
senescence (continued)
These alterations in gene expression
progressively affect the functioning of cells and
of the intercellular environment. With the
activation of telomerase, cell senescence and all
related alterations are completely canceled 1-5
cell senescence
telomerase activation
senescent cell
non-senescent cell
1 Bodnar AG et al. Extension of life-span by
introduction of telomerase into normal human
cells. Science 1998 279349-52. 2 Counter CM
et al. Dissociation among in vitro telomerase
activity, telomere maintenance, and cellular
immortalization. Proc Natl Acad Sci USA 1998
9514723-8. 3 Vaziri H. Extension of life span
in normal human cells by telomerase activation a
revolution in cultural senescence. J Anti-Aging
Med 1998 1125-30. 4 Vaziri H Benchimol S.
Reconstitution of telomerase activity in normal
cells leads to elongation of telomeres and
extended replicative life span. Curr Biol 1998
8279-82. 5 de Lange T Jacks T. For better or
worse? Telomerase inhibition and cancer. Cell
1999 98273-5.
13
on/off cell senescence and gradual cell
senescence (continued)
Telomerase gene transfection (telomerization)
is an experimental determinant, switching somatic
cells from mortal to immortal without disruption
of the remainder of gene expression This
process of gene control is central to cell aging
and experimental intervention. Resetting gene
expression occurs in knockout mice, cloning, and
other interventions, permitting us to make sense
of how cell senescence causes aging in
organisms. 1
Cells do not senesce because of wear and tear,
but because they permit wear and tear to occur
because of an altered gene expression.
Telomerization effectively replaces the score,
allowing the gene to express their previous
pattern. cells do not senesce because they are
damaged, but permit damage because they senesce.
Homeostatic processes suffice indefinitely in
germ cell lines they suffice in somatic cells if
senescence is abrogated. 1
1 Fossel MB. Cells, Aging and Human Disease.
Oxford University Press, New York 2004.
14
With the passage of time (and with very different
rhythms, varying for cell types and organs), in a
tissue - the percentage of cells in senescent
state increases - the percentage of cells with
functions more or less affected by telomere
shortening and the consequent interference in the
subtelomeric region increases.
Figure 8-2 (partial) from 1 a modicum of
cells display varying degrees of senescent
change
1 Fossel MB. Cells, Aging and Human Disease.
Oxford University Press, New York 2004.
15
This leads, for each tissue and organ, to the
atrophic syndrome, which is characterized by
1 a) reduced mean cell duplication capacity
and slackened cell turnover b) reduced number of
cells (atrophy) c) substitution of missing
specific cells with nonspecific cells d)
hypertrophy of the remaining specific cells e)
altered functions of cells with shortened
telomeres or definitively in noncycling state f)
alterations of the surrounding milieu and of the
cells depending from the functionality of the
senescent or missing cells g) vulnerability to
cancer because of dysfunctional telomere-induced
instability 2.
1 Libertini G. The Role of Telomere-Telomerase
System in Age-Related Fitness Decline, a Tameable
Process, in Telomeres Function, Shortening and
Lengthening, Nova Sc. Publ., New York 2009. 2
DePinho RA . The age of cancer. Nature 2000
408248-54.
16
AGED SKIN Human epidermis turnover is determined
by stem cells located in the dermal-epidermal
junction, a corrugated surface. In old subjects,
dermal-epidermal junction is flattened, an
indirect sign of the reduction of epidermis stem
cells, and the rate of epidermal renewal is
reduced 1. In derma, as a likely consequence
of the exhaustion of specific stem cells, a
general reduction of all its components
(melanocytes, Langerhans cells, dermal
fibroblasts, capillaries, blood vessels within
the reticular dermis, mast cells, eccrine glands,
hair. etc.) is reported and nails grow more
slowly 1.
The study of aging skin is one that presents a
paradigm for aging of other organs. 1
D-E junction
1 Griffiths CEM. Aging of the Skin. In Tallis,
RC et al. (eds), Brocklehursts Textbook of
Geriatric Medicine and Gerontology, 5th edition.
Churchill Livingstone, New York 1998.
17
AGED MUSCLE In detailed studies it has been
shown that the progressive reduction that occurs
in muscle volume with aging can be detected from
age 25 years and that up to 10 percent of muscle
volume is lost by age 50 years. Thereafter the
rate of muscle volume atrophy increases, so that
by 80 years almost half the muscle has wasted.
... Both reduction in fiber number and fiber size
are implicated in the loss of muscle volume. 1
Figure 78-4 from 2 Age-related decline in
maximum voluntary isometric force (MVF, open
symbols) and in cross-sectional area (CSA, black
symbols) in various muscles.
1 Cumming WJK. Aging and neuromuscolar disease.
In Tallis, RC et al. (eds), Brocklehursts
Textbook etc., 1998. 2 Bruce S. Muscle
strength. In Tallis, RC et al. (eds),
Brocklehursts Textbook etc., 1998.
18
AGED BONE Involutional bone loss ... starts
between the ages of 35 and 40 in both sexes, but
in women there is an acceleration of bone loss in
the decade after menopause. Overall, women lose
35 to 50 percent of trabecular and 25 to 30
percent of cortical bone mass with advancing age,
whereas men lose 15 to 45 percent of trabecular
and 5 to 15 percent of cortical bone. ... Bone
loss starts between the ages of 35 and 40 years
in both sexes, possibly related to impaired new
bone formation, due to declining osteoblast
function. 1
1 Francis RM. Metabolic Bone Disease. In
Tallis et al. (eds.), Brocklehursts textbook
etc., 1998.
19
AGED LUNG Lung volumes (FEV1, FVC) decline with
age 1. The most important age-related change
in the large airways is a reduction in the number
of glandular epithelial cells ... the area of the
alveoli falls and the alveoli and alveoli ducts
enlarge. Function residual capacity, residual
volume, and compliance increase. ... 2
young lung
senile enphysema in an old lung
1 Enright PL et al. Spirometry Reference Values
for Women and Men 65 to 85 Years of Age.
Cardiovascular Health Study. Am Rev Respir Dis
1993 147125-33. 2 Connolly MJ. Age-Related
Changes in the Respiratory System. In Tallis et
al. (eds.), Brocklehursts textbook etc., 1998.
20
AGED HEART An old and deep-rooted belief is that
the heart is an organ incapable of regeneration
and without cell turnover. But, in a normal
heart, every day about 3 million myocytes die by
apoptosis and are replaced by cardiac stem cells
the entire cell population of the heart is
replaced approximatively every 4.5 years The
human heart replaces completely its myocyte
population about 18 time during the course of
life, independently from cardiac diseases. 1.
The senile heart has a decreasing number of
myocytes owing to the progressive decline in the
ability to duplication of cardiac stem cells 1.
But the heart chambers, for lack of contractile
capacity, are dilated and, so, the senile heart,
although atrophic as number of cells, is
morphologically hypertrophic 2.
1 Anversa P et al. Life and Death of Cardiac
Stem Cells. A Paradigm Shift in Cardiac Biology.
Circulation 2006 1131451-63. 2 Aronow WS.
Effects of Aging on the Heart. In Tallis et al.
(eds.), Brocklehursts textbook etc., 1998.
21
AGED SKELETAL MUSCLE Myocytes of skeletal muscle
are cells with turnover as heart myocytes! Stem
cells from muscles of old rodents divide in
culture less than cells from muscles of young
rodents 1.   A transplanted muscle suffers
ischaemia and complete degeneration and then
there is a complete regeneration by action of
host myocyte stem cells that is poorer in
transplants from older animals 2.  In Duchenne
muscular dystrophy, there is a chronic
destruction of myocytes that are continually
replaced by the action of stem cells until these
are exhausted 3.
1 Schultz E, Lipton BH. Skeletal muscle
satellite cells changes in proliferation
potential as a function of age. Mech Age Dev
1982 20377-83. 2 Carlson BM, Faulkner JA.
Muscle transplantation between young and old
rats age of host determines recovery. Am J
Physiol 1989 256C1262-6. 3 Adams V et al.
Apoptosis in skeletal muscle. Front Biosci 2001
6D1-11.
22

• AGED ENDOTHELIUM
• The correct functionality of endothelial cells is
  essential to avoid atherogenesis and its
  complications, such as cardiac infarctions,
  cerebral ischemia and other diseases derived from
  compromised blood circulation 1. Their turnover
  is assured by endothelial progenitor cells,
  derived from bone marrow, whose number has been
  shown to be inversely related to age, reduced by
  cardiovascular risk factors (cigarette smoking,
  diabetes, hypertension, hypercholesteremia,
  etc.), and increased by drugs, such as statins,
  which protect organ integrity 1. Moreover, with
  negative relation, the number of endothelial
  progenitor cells is a predictor of cardiovascular
  risk equal to or more significant than Framingham
  risk score 1, 2.
• In the senile state, diseases deriving from a
  compromised endothelial function increase
  exponentially in correlation with the age, even
  if other cardiovascular risk factors are absent
  3. These factors anticipate and amplify the
  risk 3, while drugs with organ protection
  qualities, as statins 4, ACE-inhibitors and
  sartans 5 counter their effects.

1 Hill JM et al. Circulating endothelial
progenitor cells, vascular function, and
cardiovascular risk. N Engl J Med 2003
348593-600. 2 Werner N et al. Circulating
endothelial progenitor cells and cardiovascular
outcomes. N Engl J Med 2005 353999-1007. 3
Tallis RC et al. (eds.). Brocklehursts Textbook
of Geriatric Medicine and Gerontology, 5th ed.,
Churchill Livingstone, New York 1998. 4
Davidson MH. Overview of prevention and treatment
of atherosclerosis with lipid-altering therapy
for pharmacy directors. Am J Manag Care 2007
13S260-9. 5 Weir M.R. Effects of
renin-angiotensin system inhibition on end-organ
protection can we do better? Clin Ther 2007
291803-24.
23

• In each intestinal crypt, there are four to six
  stem cells that with their intensive duplication
  activity renew continuously the epithelium of the
  small intestine 1. In healthy old individuals,
  in comparison with young individuals the transit
  time for cells from crypts to villous tips
  decreases and villi become broader, shorter and
  with less cellularity 2. These changes, surely
  due to a declining mitotic activity of crypt stem
  cells, as hypothesised from a long time 2,
  reduce intestinal functionality and, likely,
  overall fitness.

• AGED INTESTINAL VILLI

1 Barker N et al. Identification of stem cells
in small intestine and colon by marker gene Lgr5.
Nature 2007 4491003-7. 2 Webster SGP. The
gastrointestinal system c. The pancreas and the
small bowel. In Brocklehurst, JC (ed) Textbook
of Geriatric Medicine and Gerontology (2nd ed.),
Churchill Livingstone, New York 1978.
24

• AGED LIVER
• Liver volume declines with age 1, both in
  absolute values and in proportion to body weight
  2, and this reduction has been estimated to be
  about 37 percent between ages 24 and 91 1.
  Liver blood flow also declines with age, by about
  53 percent between ages 24 and 91 1. However,
  while liver size declines with age, hepatocytes
  increase in size, unlike in the liver atrophy
  that accompanies starvation 3.
• Cirrhosis is the final stage of chronic
  destruction of hepatocytes caused by hepatitis,
  alcoholism or other factors. When hepatocyte stem
  cells exhaust their duplication capacities, the
  liver is transformed by a general atrophic
  process, often complicated by carcinomas caused
  by dysfunctional telomere-induced instability 4,
  5.

1 Marchesini G et al. Galactose Elimination
Capacity and Liver Volume in Aging Man.
Hepatology 1988 81079-83. 2 Wynne HA et al.
The Effect of Age upon Liver Volume and Apparent
Liver Blood Flow in Healthy Man. Hepatology 1989
9297-301. 3 James OFW. The Liver. In Tallis
et al. (eds.), Brocklehursts textbook etc.,
1998. 4 DePinho RA. The age of cancer. Nature
2000 408248-54. 5 Artandi SE. Telomere
shortening and cell fates in mouse models of
neoplasia. Trends Mol Med 2002 844-7.
25

• AGED BLOOD
• "... Gradual involution of red marrow continues
  but is especially marked after the age of 70
  years when iliac crest marrow cellularity is
  reduced to about 30 percent of that found in
  young adults. 1
• In vitro neutrophil functions (e. g endothelial
  adherence, migration and phagocytosis capacity,
  granule secretory behavior, etc.) are
  insignificantly affected by age but in vivo
  significantly fewer neutrophils arrive at the
  skin abrasion sites studied in older people 2.
  The proliferative capacity of T lymphocytes to
  nonspecific mitogens is greatly reduced with
  aging 3.
• It has been suggested that age-related functional
  decline in adult tissue hematopoietic stem cells
  limits longevity in mammals 4.

1 Gilleece MH, Dexter TM. Aging and the Blood.
Tallis et al. (eds.), Brocklehursts textbook
etc., 1998. 2 MacGregor RR, Shalit M.
Neutrophil Function in Healthy Elderly Subjects.
J Gerontol 1990 45M55-60. 3 Gravenstein S,
Fillit H, Ershler WB. Clinical Immunology of
Aging. Tallis et al. (eds.), Brocklehursts
textbook etc., 1998. 4 Geiger H. and Van Zant
G. The aging of lympho-hematopoietic stem cells.
Nat. Immunol. 2002 3329-33.
26

• AGED KIDNEY
• Age-induced renal changes are manifested
  macroscopically by a reduction in weight of the
  kidney and a loss of parenchymal mass. The
  decrease in weight of the kidneys corresponds to
  a general decrease in the size and weight of all
  organs. Microscopically, the most impressive
  changes are reductions in the number and size of
  nephrons. Loss of parenchymal mass leads to a
  widening of the interstitial spaces between the
  tubules. There is also an increase in the
  interstitial connective tissue with age. The
  total number of identifiable glomeruli falls with
  age, roughly in accord with the changes in renal
  weight. 1
• Microalbuminuria, a simple marker of nephropathy,
  is predictive, independently of traditional risk
  factors, of all-cause and cardiovascular
  mortality and CVD events within groups of
  patients with diabetes or hypertension, and in
  the general population ... It may ... signify
  systemic endothelial dysfunction that predisposes
  to future cardiovascular events 2, and this
  implicates that drugs effective in organ
  protection defend renal functionality too.

1 Jassal V et al. Aging of the Urinary Tract.
Tallis et al. (eds.), Brocklehursts textbook
etc., 1998. 2 Weir MR. Microalbuminuria and
cardiovascular disease. Clin J Am Soc Nephrol
2007 2581-90.
27
Cell types without turnover
AGED RETINAL NERVOUS CELLS Photoreceptor cells
(cones and rods) are highly differentiated
nervous cells with no turnover, but metabolically
depending on other cells with turnover, retina
pigmented cells (RPC), which are highly
differentiated gliocytes. Without the macrophagic
activity of RPC, photoreceptor cells cannot
survive 1.
The age-related decline or RPC turnover causes
the death of photoreceptor cells, which is more
clinically evident in macula function
(age-related macular degeneration or ARMD). ARMD
affects 5, 10 and 20 of subjects 60, 70 and 80
years old, respectively 1, and it is likely
that a large proportion of older individuals
suffer from ARMD. 
1 Berger JW et al. Age-related macular
degeneration, Mosby, USA 1999.
28
AGED NEURONS OF THE CENTRAL NERVOUS SYSTEM The
neurons depend on particular types of gliocytes
(microglia cells). Microglia cells degrade
ß-amyloid protein 1, 2 and this function is
known to be altered in Alzheimer Disease (AD) 3
with the consequent noxious accumulation of the
protein. The hypothesis that AD is caused by the
declining turnover of microglia cells has been
proposed 4-7.
1 Qiu WQ et al. Insulin-degrading enzyme
regulates extracellular levels of amyloid
beta-protein by degradation. J Biol Chem 1998
27332730-8. 2 Vekrellis K et al. Neurons
regulate extracellular levels of amyloid
beta-protein via proteolysis by insulin-degrading
enzyme. J Neurosci 2000 201657-65. 3 Bertram
L et al. Evidence for genetic linkage of
Alzheimer's disease to chromosome 10q. Science
2000 2902302-3. 4 Fossel MB. Reversing Human
Aging. William Morrow and Company, New York
1996. 5 Fossel MB. Cells, Aging and Human
Disease. Oxford University Press, New York
2004. 6 Libertini G. Prospects of a Longer Life
Span beyond the Beneficial Effects of a Healthy
Lifestyle, Ch. 4 in Handbook on Longevity
Genetics, Diet Disease, Nova Sc. Publ., New
York 2009. 7 Flanary B. Telomeres Function,
Shortening, and Lengthening, in Telomeres
Function, Shortening and Lengthening, Nova
Science Publishers Inc., New York 2009.
29
AGED EYE CRYSTALLINE LENS The crystalline lens
has no cell in its core, but its functionality
depends on lens epithelial cells that show
turnover 1. Many investigators have
emphasized post-translational alterations of
long-lived crystalline proteins as the basis for
senescent ocular cataracts. It is apparent in
Werner syndrome that the cataracts result from
alterations in the lens epithelial cells 2,
which is consistent with age-related reduction in
growth potential for lens epithelial cells
reported for normal human subjects 1. Smoke and
diabetes are risk factors for cataract
3. Statins lower the risk of cataract 4. This
has been attributed to putative antioxidant
properties 4, but could be the consequence of
effects on lens epithelial cells analogous to
those on endothelial cells 5.
1 Tassin J et al. Human lens cells have an in
vitro proliferative capacity inversely
proportional to the donor age. Exp. Cell Res.
1979 123388-92. 2 Martin GM Oshima J.
Lessons from human progeroid syndromes. Nature
2000 408263-6. 3 Delcourt C et al. Risk
factors for cortical, nuclear, and posterior
subcapsular cataracts the POLA study.
Pathologies Oculaires Liées à l'Age. Am J
Epidemiol 2000 151497-504. 4 Klein BE et al.
Statin use and incident nuclear cataract. JAMA
2006 2952752-8. 5 Hill JM et al. Circulating
endothelial progenitor cells, vascular function,
and cardiovascular risk. N. Engl. J. Med 2003
348593-600.
30
Programmed cell death, cell senescence (on/off
and gradual), cell duplication limits (variable
according to cell types and influenced by
various physiological and pathological events),
cell turnover and its limitations (variable
depending on the cell types) are all phenomena
genetically determined and regulated.
31
Some features of these phenomena have no
justification in terms of physiological factors
other than aging.
In particular, the supporters of Old Paradigm try
to justify the limits in cell replication as a
general defense against cancer 1,2. But -
Species with negligible senescence (i.e., with
individuals showing no age-related decay) have no
age-related reduction of telomerase activity and
no increase in mortality due to cancer 3. - In
the human species, studied under natural
conditions, fitness decline (i.e., aging) reaches
significant levels without a detectable incidence
of cancer mortality. It is untenable that a
defense against cancer kills large part of the
population before cancer as cause of death
becomes detectable 4.
1 Campisi J. The biology of replicative
senescence. Eur J Cancer 1997 33(5)7039. 2
Wright WE Shay JW. Telomere biology in aging
and cancer. J Am Geriatr Soc 2005 53(9
S)S2924. 3 Libertini G. Empirical evidence
for various evolutionary hypotheses on species
demonstrating increasing mortality with
increasing chronological age in the wild. The
Scientific World Journal 2008 8182-93. 4
Libertini G. Evidence for Aging Theories from the
Study of a HunterGatherer People (Ache of
Paraguay). Biochem (Mosc) 2013 78(9)1023-32.
32
Conclusion

• The mechanisms, genetically determined and
  regulated, here summarized, clearly cause the
  age-related progressive deterioration of all
  functions, namely aging. They are predicted by
  the New Paradigm and indeed are essential for its
  validity.
• On the contrary, they are not expected by the Old
  Paradigm and are in complete contrast with it.
• The explanation of aging through the New Paradigm
  allows
• - A rational and consistent interpretation of all
  the manifestations of aging
• The prospect of being able to change and obtain
  a full control of aging through scientific
  procedures which are technically feasible 1,2.

1 Libertini G. Prospects of a Longer Life Span
beyond the Beneficial Effects of a Healthy
Lifestyle, Ch. 4 in Handbook on Longevity
Genetics, Diet Disease, Nova Science Publishers
Inc., New York 2009. 2 Libertini G. The Role of
Telomere-Telomerase System in Age-Related Fitness
Decline, a Tameable Process, in Telomeres
Function, Shortening and Lengthening, Nova Sc.
Publ., New York 2009.
33
Conclusion (continued)
The exposition and discussion of this last
prospect, already briefly expounded elsewhere
1, is however outside and beyond the limits of
time and of topic of this oral presentation. I
do only dare to say
The possibility of an unlimited lifespan - until
now was excluded by prejudices, - today is a
choice, - tomorrow will be restrained by the
ability to endure an unlimited life. 
1 Libertini G. Prospects of a Longer Life Span
beyond the Beneficial Effects of a Healthy
Lifestyle, Ch. 4 in Handbook on Longevity
Genetics, Diet Disease, Nova Science Publishers
Inc., New York 2009.
34
This presentation is on my personal pages too
www.r-site.org/ageing. (e-mail
giacinto.libertini_at_tin.it)
Thanks for your attention