AgingTaming
(alias Project “Homo sapiens liberatus II” [1])
To control thoroughly aging process by a well defined ambitious plan that considers the phenomenon a function genetically determined and regulated
by Giacinto Libertini
Sections
Introduction
Non-scientific issues related to the program
Distinction between aging and diseases caused by other factors
Physiology of aging
-- Concept 1 (telomere shortening and impaired gene expression)
-- Concept 2 (cycling / non-cycling cells, cell senescence)
-- Concept 3 (cell turnover)
-- Concept 4 (importance of relative and not absolute shortening of telomeres)
-- Concept 5 (species-specific regulation of telomere-telomerase system)
-- Atrophic state
-- Cells without turnover
-- Description of aging in tissues and organs of our species
AgingTaming Program
Specific problems
--Insertion of DNA sequences
-- Telomerase activation and cancer risk
-- Three important recent experiments
-- Teeth wear
-- ARMD and AD treatment
What does the proposition of this program mean in the context of Lifeboat Foundation?
Introduction
In the current paradigm, aging is not conceived as a distinct process but as the sum of many degenerative phenomena insufficiently opposed by natural selection and caused by:
- effects of harmful mutations accumulated from generation to generation and that cannot be sufficiently contrastedby the natural selection because they express themselves at ages when few survive (mutation accumulation theory [2-6]);
- genes that are advantageous at younger ages and harmful at older ages (antagonistic pleiotropy theory [7,8]);
- genes that cannot be eliminated or blocked in their actions as a result of physiological, biochemical or environmental constraints (disposable soma theory [9,10]).
These theories may be summarized in the idea that aging manifestations demonstrate howevolution has severe limits, or, in other words, that aging is the main failure of evolution.
Hence the concept that aging is something inexorable and will never be defeated: at most, we can hope to restrain it,increasing lifespan but also prolonging the sufferings and disabilities of old age.
This conception also implies that in the current International Statistical Classification of Diseases and Related Problems (ICD-10 [11]) (and in the previous classifications) there is no code for aging phenomenon but many codes for old age diseases. In short, according to this view, nobody, not even a centenarian, dies byaging but allthe men always die by other causes!
To this conception and its implications, which for brevity I call "old paradigm", an entirely different conception ("new paradigm") is opposed: aging is a distinct physiological phenomenon, with its evolutionary causes, physiological mechanisms, pathology and phylogeny.
According to the new paradigm, the old men die by aging function, a statement which might seem a banal quip but that for the cultured supporters of the old paradigm is clearly a serious heresy which is widespread among the uneducated man but unacceptable for any serious scientist.
Moreover, according to the new paradigm, aging is not an example of evolution failure, but another triumph of evolution: it is a very sophisticated function that is perfectly explicable in terms of supra-individual selection in particular ecological conditions (in short, social species with spatial distribution of its individuals).
As interesting corollaries, we have that:
a) species not in certain ecological conditions, are predicted by the theory that will not age;
b) as aging is a function, it is, in principle, something controllable, even totally.
The newparadigm makes the present programa concrete and not utopian or unrealistic proposal.
In a subsequent section, the physiology of aging, i.e. its mechanisms, will be explained in general terms.
As for a brief but documented distinction between "old" and "new" paradigm, I advice to see a poster that I presented in 2010 [12].
Regarding the concept of aging as a phenomenon programmed and genetically determined and regulated, it is possible to consult a site dedicated to it [13].
To know a theory that specifically tries to explain aging as a phenomenon favored by evolution, I advice the theory personally proposed by myself [14-18].
For some empirical arguments that contrast the old paradigm and support the new paradigm, see [19,20].
As for a discussion in terms of philosophy of science against the old paradigm and in support of the new paradigm, I suggest to read an interesting article [21].
Concerning the pathology of aging, you can read the section “Two Wrong Performances: Dyskeratosis Congenita and Werner Syndrome” in [17] and the chapters devoted to this topic in any good textbook of pathology.
Concerning the phylogeny of age-related fitness decline (a more correct and less equivocal way to say aging), it is possible to read a paper dedicated to it [22].
However, I strongly suggest to deal with the subjects of pathology and phylogeny of aging only after having understood the physiology of the phenomenon.
I must also add that aging should be viewed in the more general context of phenoptotic phenomena, where "phenoptosis" (Skulachev 1997 [23]) is the “programmed death of an individual” and aging, defined by the same Skulachev as "slow phenoptosis" [24], is one among many types of phenoptosis.
For a classification of the various types of phenoptosis, see [25]. To better evaluate the importance of the classification of aging under phenoptotic phenomena, see [26].
Finally, as regards species that do not show the aging phenomenon, see: a)chapter 4, dedicated to the animals with "negligible senescence", in the textbook of Finch [27]; b)the section “A Surprising Cue: Animals with Negligible Senescence” in [17]; c) a site dedicated to "ageless animals" [28] (see Fig. 1 too).
Figure 1 - A specimen of rockfish, a group of species that show no age-related alteration. Image from the site dedicated to: Emerging Area of Aging Research: Long-lived Animals with "Negligible Senescence" [28].
Non-scientific issues related to the program
This program does not address the possible serious questions and problems of ethical, philosophical, religious, economic, social, cultural nature related to itsproposing, planning and implementing.
Some mentions of them are exposed in the section “Characteristics of Age with a Future Unlimited Longevity” in [18].
However, while admitting without doubts the existence of serious questions and problems of the aforementioned type, and although we could share, in principle, some of them, it is necessary to specify that the program does not include the formulation, analysis or discussion of them.
The program is based on the clear choice, which is volitive and not scientific, of pursuing the goal of controlling the aging process in order to extend maximum lifespan in a state of youthful health.
Therefore, anyone may well criticize or reject, out of here, the choice made, but it is not appropriate, and they will not be accepted here,to formulate contributions or criticisms about the issues mentioned above, or in general about the decision underlying the program.
Distinction between aging and diseases caused by other factors
In old age, we suffer by many diseases that are caused or accelerated and aggravated by harmful lifestyles.
For example, a diet that is rich in fat and calories and a sedentary lifestyle cause atherosclerosis and its complications in unusual ages for people with a more correct way of life. But, since one of the characteristics of old age is the atherosclerosis of the arteries, it is easy to confuse the effects of a damaging lifestyle with the physiological manifestations of aging.
Another confusion arises from the fact that with a healthy lifestyle and modern medical care, it is possible to reduce the aforesaid diseases and increase the survival, creating the false illusion of a partially counteracted aging.
More precisely, with a healthy lifestyle and the abovementioned care we counter some of the diseases that are associated to aging but not aging in itself.
These arguments are better and more fully exposed in [18].
Physiology of aging
-- Concept 1 (telomere shortening and impaired gene expression)
In correlation with the progressive relative shortening of telomeres, the expression of many genes, among those usually expressed in the cell, becomes impaired, jeopardizing overall cell functionality and, consequently, the functions of extracellular matrix and of other near or physiologically interdependent cells. [17,36].
About the underlying mechanism, see chapter 3 in [36], the section “The Protagonist: Telomere-Telomerase System” in [17], and the concept that “Cells do not senesce because of wear and tear, but because of an altered pattern of gene expression. Telomerization effectively replaces the score, allowing the genes to express their previous pattern.” [36]
-- Concept 2 (cycling / non-cycling cells, cell replicative senescence)
Somatic cells may be in two different conditions.
A) The first (cycling or non-senescent state) is characterized by the ability to replicate and by the absence of the biochemical and morphological characteristics of senescent cells.
B) The second (non-cycling or senescent state) is characterized by the absence of replication capacities and by the presence of those alterations that are characteristics of senescent cells.
The transition from cycling to non-cycling state is an event inversely related to the length of telomeres, the terminal part of the DNA molecules. The event, which is an all-or-nothing phenomenon, becomes more and more probable as telomeres shorten at each cell replication but there is no telomere length that inhibits it [29].
The transformation from the first to the second state, also commonly called "cell senescence", or – more precisely - replicative senescence, determines complex modifications in gene expression patterns and the secretion of various substances, inflammatory cytokines included, which alter the interstitial fluid and the function of neighboring cells. As these changes are stereotyped and predictable, cell senescence has been described as a “fundamental cellular program” [30].
The above said changes are a consequence of this program and not the cause of it. The programmed nature of them is clearly demonstrated by their complete reversibility. In fact, the activation of telomerase undoes senescence state and returns the cells to non-cycling state [31-35].
However, the gradual increase in a tissue or organ of the number of cells with impaired gene expression and/or in replicative senescence causes the gradual transition from young to old condition [29,36].
-- Concept3 (cell turnover)
In a tissue or organ, cells die continuously for various types of programmed cell death (PCD), in particular by apoptosis, a phenomenon of extreme importance but described only in 1972 [37] and that affects all adult tissues (see the section "The Other Protagonist: Programmed Cell Death "in [17]), apart from its importance for morphogenesis and other phenomena.
The continuous loss of cells by apoptosis and other types of PCD is perfectly balanced in the young individual by an incessant duplication of stem cells of various levels, with variable replication ratesand capacities depending on cell types, tissues and organs.
“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” [38].
This continuous cell turnover, a phenomenon very articulated and finely regulated, slows down progressively with age as duplication capacity of stem cells runs out by reduction of telomere length, a parameter under the control of telomere-telomerase system. This, together with the progressive increase of the number of cells with impaired gene expression and/or in replicative senescence, results in a growing atrophy of tissues and organs, and a decrease of their functionality [17,36]. This condition ("atrophic state") is described in a later section.
-- Concept 4 (importance of relative and not absolute shortening of telomeres)
The phenomenon of activation of cell senescence, and so the block of cell replication capacities, is in function not of the absolute length of telomeres but of their relative shortening [17,36].
-- Concept 5 (species-specific regulation of telomere-telomerase system)
The difference in longevity among species is not a function of absolute telomere length but of the species-specific regulation of telomere-telomerase system [17,36].
-- Atrophic state
In its general lines, the atrophic state of a tissue or organ may be thus briefly described [17]:
a) block of cell duplication capacity in senescent cells;
b) reduced number of cells (atrophy);
c) slackened cell turnover;
d) possible substitution of missing specific cells with nonspecific cells;
e) hypertrophy of the remaining specific cells;
f) altered functions of cells with shortened telomeres or definitively in non-cycling state;
g) altered interstitial liquid caused by senescent cells with damage for neighboring cells;
h) vulnerability to cancer because of dysfunctional telomere-induced instability [39].
-- Cells without turnover
The general pattern described above may seem wholly inapplicable to cells and organs with no turnover, i.e.eye crystalline lens, neurons, and retina rods and cones (which are highly differentiated neurons).
But crystallinelens, neurons and retina rods and conesare dependent for their trophism on lens epithelial cells, microglial cells and retina pigmented cells, respectively. All these trophic cells show apoptosis and cell turnover, and when their renewal is inadequate you have cataracts [17], Alzheimer's disease (AD) [17,36,40,41] and age-related macular degeneration (ARMD) [17], respectively (see [42] for an illustrated explanation, and fig. 2).
Figure 2 - Schemes of retina photoreceptors and of a brain neuron (both neurons) served by two types of differentiated gliocytes, retina pigmented cells and microglia cells, respectively. Cell senescence of retina pigmented cells and of microglia cells cause age-related macular degeneration and Alzheimer disease, respectively [18].
-- Description of aging in tissues and organs of our species
A concise but documented description of the aging of various organs and tissues in our species is given in the section "The Main Action: Aging in Man" in [17] and in [18] and I refer to them for the topic and the references cited therein (see figures 3 and 4 too).
Figure 3 - Normal lung (left) in comparison with a lung affected by marked senile emphysema (right) [17].
Figure 4 - Intestinal villi in young and older individuals [18].
AgingTaming Program
With some small differences, the program was proposed in 2009 [18], and presented as poster in 2010 with the name “Homo sapiens liberatus II” as a due homage to Prof. Skulachev [1].
As basic idea, it is indispensable to acquire the awareness that aging is a function and not the sum of heterogeneous degenerative phenomena. By considering correctly aging a function, it is possible to conceive an ambitious program for the control of the phenomenon in four steps (which may partially overlap):
Step 1
Parallel pursuit of various targets (duration: 5-15 years)
a) Widening of the studies on the telomere-telomerase system;
b) The same for apoptosis phenomenon;
c) The same for cell turnover of all tissues and its effect on the functions of the organs;
d) The same for the morphogenesis of the organs, in particular for the dentition;
e) Development of genetic techniques for the effective and precise insertion of a genetic sequence in a point of the genome not causing dangerous alterations;
f) Development of genetic techniques for the effective and precise substitution of a genetic sequence with another sequence;
g) Research of possible safe drugs to modify the telomere-telomerase system and/or cell turnover (or other) so that longevity is increased.
Step 2
Parallel pursuit of various targets (duration: 5-15 years)
a) Experiments on animals of insertion of genetic sequences to modify the modulation of the telomere-telomerase system for increasing longevity;
b) The same with techniques of genetic substitution;
c) First applications of the above-mentioned techniques for the treatment of severe genetic diseases;
d) First applications of the above-mentioned techniques for the treatment of age-related severe diseases such as age-related macular degeneration and Alzheimer’s disease;
e) As with (a) and (b) to obtain multiple dentitions;
f) Experiments on animals of possible drugs with increasing longevity qualities.
Step 3
Duration: at least two decades
a) First experiments on man of gene modifications (but not on germinal cells) and of possible drugs with increasing longevity qualities;
b) Verification of the results and progressive widening of the experiments.
Step 4
Duration: indeterminate
a) Possible experimentation and application of gene modifications on human germinal cells;
b) Applications on a large scale of safe and tested techniques and drugs.
Specific problems
-- Insertion of DNA sequences
In order to modify the genetic mechanisms that modulate aging, it is essential to introduce gene sequences into the DNA of an individual. In general, this is possible using two types of approaches already shown elsewhere [18].
Using the first approach, the DNA is introduced by viral vectors in random points of the genome and in cells randomly transformed by the virus. This approach, already used for the treatment of certain genetic diseases, has limitations [43] and involves the danger that an insertion may inactivate a suppressor oncogene and arouse cancer (insertional oncogenesis) [44] (Fig. 5).
Using the second approach, the DNA is inserted in a precise point of the genome, through the use of guide sequences of annealing. This allows to avoid the oncogene risk. Moreover, since the point of insertion is unique, you can modify a large percentage of cells thus affecting the stem cells with a lasting effect (see Figures 6 and 7).
Figure 5 - Current gene therapy. DNA sequence is inserted in a random position by a vector virus. If an insertion inactivates a suppressor oncogene, this may cause a cancer. The type of vector virus and/or limits in the dose of viruses inoculated may cause the transformation only of differentiated cells and not of the rare stem cells and, consequently, the transitory success of the therapy, because cell turnover gradually substitutes differentiated cells with new cells originated from non-transformed stem cells.