The stem cell theory of aging postulates that the aging process is the result of the inability of various types of stem cells to continue to replenish the tissues of an organism with functional differentiated cells capable of maintaining that tissue's (or organ's)
original function. Damage and error accumulation in genetic material is
always a problem for systems regardless of the age. The number of stem
cells in young people is very much higher than older people and this
cause a better and more efficient replacement mechanism in the young
contrary to the old. In other words, aging is not a matter of the
increase of damage, but a matter of failure to replace it due to
decreased number of stem cells. Stem cells decrease in number and tend
to lose the ability to differentiate into progenies or lymphoid lineages and myeloid lineages.
Maintaining the dynamic balance of stem cell pools requires several conditions. Balancing proliferation and quiescence along with homing and self-renewal of hematopoietic stem cells are favoring elements of stem cell pool maintenance while differentiation, mobilization and senescence are detrimental elements. These detrimental effects will eventually cause apoptosis.
There are also several challenges when it comes to therapeutic use of stem cells and their ability to replenish organs and tissues. First, different cells may have different lifespans even though they are originated from the same stem cells, meaning that aging can occur differently in cells that have longer lifespans as opposed to the ones with shorter lifespans. Also, continual effort to replace the somatic cells may cause exhaustion of stem cells.
There are also several challenges when it comes to therapeutic use of stem cells and their ability to replenish organs and tissues. First, different cells may have different lifespans even though they are originated from the same stem cells, meaning that aging can occur differently in cells that have longer lifespans as opposed to the ones with shorter lifespans. Also, continual effort to replace the somatic cells may cause exhaustion of stem cells.
Research
Some of the proponents of this theory have been Norman E. Sharpless, Ronald A. DePinho, Huber Warner, Alessandro Testori and others. Warner came to this conclusion after analyzing human case of Hutchinson's Gilford syndrome and mouse models of accelerated aging.
Stem cells will turn into certain cells as the body needs them.
Stem cells divide more than non stem cells so the tendency of
accumulating damage is greater. Although they have protective
mechanisms, they still age and lose function. Matthew R. Wallenfang,
Renuka Nayak and Stephen DiNardo showed this in their study. According
to their findings, it is possible to track male GSCs labeled with lacZ gene in Drosophila
model by inducing recombination with heat shock and observe the
decrease in GSC number with aging. In order to mark GSCs with lacZ gene,
flip recombinase (Flp)-mediated recombination is used to combine a
ubiquitously active tubulin promoter followed by an FRT (flip recombinase target) site with a promotorless lacZ ORF (open reading frame)
preceded by an FRT site. Heat shock is used to induce Flp recombinase
marker gene expression is activated in dividing cells due to
recombination. Consequently, all clone of cells derived from GSC are
marked with a functional lacZ gene. By tracking the marked cells, they
were able to show that GSCs do age.
Another study in a mouse model shows that stem cells do age and
their aging can lead to heart failure. Findings of the study indicate
that diabetes leads to premature myocyte senescence and death and together they result in the development of cardiomyopathy due to decreased muscle mass.
Behrens et al.
have reviewed evidence that age-dependent accumulation of DNA damage in
both stem cells and cells that comprise the stem cell microenvironment
is responsible, at least in part, for stem cell dysfunction with aging.
Hematopoietic stem cell aging
Hematopoietic stem cells (HSCs) regenerate the blood system throughout life and maintain homeostasis . DNA strand breaks accumulate in long term HSCs during aging. This accumulation is associated with a broad attenuation of DNA repair and response pathways that depends on HSC quiescence. DNA ligase 4 (Lig4) has a highly specific role in the repair of double-strand breaks by non-homologous end joining (NHEJ). Lig4 deficiency in the mouse causes a progressive loss of HSCs during aging. These findings suggest that NHEJ is a key determinant of the ability of HSCs to maintain themselves over time.
Hair follicle stem cell aging
A key aspect of hair loss with age is the aging of the hair follicle.
Ordinarily, hair follicle renewal is maintained by the stem cells
associated with each follicle. Aging of the hair follicle appears to be
primed by a sustained cellular response to the DNA damage that
accumulates in renewing stem cells during aging. This damage response involves the proteolysis of type XVII collagen by neutrophil elastase
in response to the DNA damage in the hair follicle stem cells.
Proteolysis of collagen leads to elimination of the damaged cells and
then to terminal hair follicle miniaturization.
Evidence against the theory
Diseases such as Alzheimer's disease,
end-stage renal failure and heart disease are caused by different
mechanisms that are not related to stem cells. Also, some diseases
related to hematopoietic system, such as aplastic anemia and complete bone marrow failure, are not especially age-dependent. Aplastic Anemia is often an adverse effect of certain medications but as such it cannot really be considered as evidence against the stem
cell theory of aging. The cellularity of the bone marrow does decrease
with age and can be usually calculated by the formula 100-age, and this
seems consistent with a stem cell theory of aging . A dog study published by Zaucha J.M, Yu C. and Mathioudakis G., et al.
also shows evidence against the stem cell theory. Experimental
comparison of the engraftment properties of young and old marrow in a
mammal model, the dog, failed to show any decrement in stem cell
function with age.
Other theories of aging
The aging process can be explained with different theories. These are evolutionary theories, molecular theories, system theories and cellular theories. The evolutionary theory of ageing was first proposed in the late 1940s and can be explained briefly by the accumulation of mutations (evolution of ageing), disposable soma and antagonistic pleiotropy hypothesis. The molecular theory of ageing includes phenomena such as gene regulation (gene expression), codon restriction, error catastrophe, somatic mutation (accumulation of genetic material damage) and dysdifferentiation (DNA damage theory of aging). The system theories include the immunologic approach to ageing, rate-of-living and the alterations in neuroendocrinal control mechanisms. (Seehomeostasis). Cellular theory of ageing can be categorized as telomere theory, free radical theory (free-radical theory of aging) and apoptosis. The stem cell theory of aging is also a sub-category of cellular theories.
