How we age according to
Programmed Aging Paradigm
Giacinto Libertini
giacinto.libertini@tin.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
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 supraindividual 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; 408:233-8.
[3] Libertini G. Empirical evidence for various evolutionary hypotheses on species demonstrating increasing
mortality with increasing chronological age in the wild. TheScientificWorld Journal 2008; 8:183-93.
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
Hormonally triggered
senescence in plants
Death after
spawning
Death of the male associated
with mating / reproduction
Aging (“slow
phenoptosis” [4])
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;
959:214-37.
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;
8:183-93.
[2] Kirkwood TBL, Austad SN. Why do we age? Nature 2000; 408:233-8.
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; 26:239-57.
[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.
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; 17:2941-53.
Duplication of stem cells
CELL TURNOVER
Cell death by PCD
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).
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
[1] Alberts B. et al. Essential Cell Biology, 4° ed., Garland Science, 2013.
QUICK
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;
25:585-621.
[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; 41:181-90.
[3] Blackburn EH & Gall JG. A tandemly repeated sequence at the termini of the extrachromosomal
ribosomal RNA genes in Tetrahymena. J Mol Biol 1978; 120:33-53.
[4] Greider CW & Blackburn EH. Identification of a specific telomere terminal transferase activity in
Tetrahymena extracts. Cell 1985; 51:405-13.
[5] van Steensel B & de Lange T. Control of telomere length by the human telomeric protein TRF1. Nature
1997; 385:740-3.
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 noncycling 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; 408:53-6.
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; 37:961–76.
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.
“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
non-senescent cell
senescent cell
[1] Bodnar AG et al. Extension of life-span by introduction of telomerase into normal human cells. Science
1998; 279:349-52.
[2] Counter CM et al. Dissociation among in vitro telomerase activity, telomere maintenance, and cellular
immortalization. Proc Natl Acad Sci USA 1998; 95:14723-8.
[3] Vaziri H. Extension of life span in normal human cells by telomerase activation: a revolution in cultural
senescence. J Anti-Aging Med 1998; 1:125-30.
[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; 8:279-82.
[5] de Lange T & Jacks T. For better or worse? Telomerase inhibition and cancer. Cell 1999; 98:273-5.
“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.
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.
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; 408:248-54.
AGED SKIN
Human epidermis turnover is determined by stem cells located in the dermalepidermal 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]
[1] Griffiths CEM. Aging
of the Skin. In: Tallis, RC
et al. (eds), Brocklehurst’s
Textbook
of
Geriatric
Medicine and Gerontology,
5th
edition.
Churchill
Livingstone, New York
1998.
D-E
junction
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), Brocklehurst’s Textbook
etc., 1998.
[2] Bruce S. Muscle strength. In:
Tallis, RC et al. (eds), Brocklehurst’s
Textbook etc., 1998.
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.), Brocklehurst’s textbook etc.,
1998.
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; 147:125-33.
[2] Connolly MJ. Age-Related Changes in the Respiratory System. In: Tallis et al. (eds.),
Brocklehurst’s textbook etc., 1998.
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; 113:1451-63.
[2] Aronow WS. Effects of Aging on the Heart. In: Tallis et al. (eds.), Brocklehurst’s textbook
etc., 1998.
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; 20:377-83.
[2] Carlson BM, Faulkner JA. Muscle transplantation between young and old rats: age of
host determines recovery. Am J Physiol 1989; 256:C1262-6.
[3] Adams V et al. Apoptosis in skeletal muscle. Front Biosci 2001; 6:D1-11.
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; 348:593-600.
[2] Werner N et al. Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med
2005; 353:999-1007.
[3] Tallis RC et al. (eds.). Brocklehurst’s 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; 13:S260-9.
[5] Weir M.R. Effects of renin-angiotensin system inhibition on end-organ protection: can we do better?
Clin Ther 2007; 29:1803-24.
AGED INTESTINAL VILLI
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.
[1] Barker N et al. Identification of stem cells in small intestine and colon by marker gene
Lgr5. Nature 2007; 449:1003-7.
[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.
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; 8:1079-83.
[2] Wynne HA et al. The Effect of Age upon Liver Volume and Apparent Liver Blood Flow in
Healthy Man. Hepatology 1989; 9:297-301.
[3] James OFW. The Liver. In: Tallis et al. (eds.), Brocklehurst’s textbook etc., 1998.
[4] DePinho RA. The age of cancer. Nature 2000; 408:248-54.
[5] Artandi SE. Telomere shortening and cell fates in mouse models of neoplasia. Trends Mol
Med 2002; 8:44-7.
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.), Brocklehurst’s textbook
etc., 1998.
[2] MacGregor RR, Shalit M. Neutrophil Function in Healthy Elderly Subjects. J Gerontol
1990; 45:M55-60.
[3] Gravenstein S, Fillit H, Ershler WB. Clinical Immunology of Aging. Tallis et al. (eds.),
Brocklehurst’s textbook etc., 1998.
[4] Geiger H. and Van Zant G. The aging of lympho-hematopoietic stem cells. Nat. Immunol.
2002; 3:329-33.
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.), Brocklehurst’s textbook etc.,
1998.
[2] Weir MR. Microalbuminuria and cardiovascular disease. Clin J Am Soc Nephrol 2007;
2:581-90.
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.
AGED NEURONS OF THE
CENTRAL NERVOUS SYSTEM
The neurons depend on particular
types of gliocytes (microglia cells).
Microglia cells degrade β-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; 273:32730-8.
[2] Vekrellis K et al. Neurons regulate extracellular levels of amyloid beta-protein via proteolysis by insulindegrading enzyme. J Neurosci 2000; 20:1657-65.
[3] Bertram L et al. Evidence for genetic linkage of Alzheimer's disease to chromosome 10q. Science 2000;
290:2302-3.
[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.
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; 123:388-92.
[2] Martin GM & Oshima J. Lessons from human progeroid syndromes. Nature 2000; 408:263-6.
[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; 151:497-504.
[4] Klein BE et al. Statin use and incident nuclear cataract. JAMA 2006; 295:2752-8.
[5] Hill JM et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular
risk. N. Engl. J. Med 2003; 348:593-600.
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.
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):703–9.
[2] Wright WE & Shay JW. Telomere biology in aging and cancer. J Am Geriatr Soc 2005; 53(9 S):S292–4.
[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;
8:182-93.
[4] Libertini G. Evidence for Aging Theories from the Study of a Hunter–Gatherer People (Ache of
Paraguay). Biochem (Mosc) 2013; 78(9):1023-32.
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.
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.
This presentation is on my personal pages too:
www.r-site.org/ageing.
(e-mail: giacinto.libertini@tin.it)
Thanks
for your attention