Revisiting telomere shortening yet-again

After coming up from burying myself for a month in the research leading to the Stem Cell Supply Chain Breakdown theory of aging, I decided to check on recent research relating this theory to the Telomere Shortening and Damage theory of aging.  I found a treasure trove of recent publications which shed light on three issues: the relationship between the two theories, the role of telomere shortening in multiple disease processes, and the nature of telomere shortening.  I report on these here.

Stem cells and telomere shortening

The two theories actually fit together hand-in-glove. A number of studies suggest that a main cause for depletion of pools of stem cells and deterioration of the ability of stem cells in those pools to differentiate is shortened stem cell telomeres due to replicative senescence.  Except for embryonic stem cells, somatic stem cells and progenitor cells (Types B and C according to my theory) are subject to telomere shortening due to continuing replication.  Quoting from different research studies:

1.     Somatic stem cells lose telomere length on replication

·        “– the level of telomerase activity is low or absent in the majority of stem cells regardless of their proliferative capacity. Thus, even in stem cells, except for embryonal stem cells and cancer stem cells, telomere shortening occurs during replicative ageing, possibly at a slower rate than that in normal somatic cells(ref).”

·        “–telomere length, as well as the catalytic component of telomerase, Tert, are critical determinants in the mobilization of epidermal stem cells. Telomere shortening inhibited mobilization of stem cells out of their niche, impaired hair growth, and resulted in suppression of stem cell proliferative capacity in vitro(ref).” 

·        “– telomerase activity and telomere length can directly affect the ability of stem cells to regenerate tissues. If this is true, stem cell dysfunction provoked by telomere shortening may be one of the mechanisms responsible for organismal aging in both humans and mice(ref).”

·        “The proliferative life-span of the stem cells that sustain hematopoiesis throughout life is not known. It has been proposed that the sequential loss of telomeric DNA from the ends of human chromosomes with each somatic cell division eventually reaches a critical point that triggers cellular senescence. We now show that candidate human stem cells with a CD34+CD38lo phenotype that were purified from adult bone marrow have shorter telomeres than cells from fetal liver or umbilical cord blood. We also found that cells produced in cytokine-supplemented cultures of purified precursor cells show a proliferation-associated loss of telomeric DNA. These findings strongly suggest that the proliferative potential of most, if not all, hematopoietic stem cells is limited and decreases with age, a concept that has widespread implications for models of normal and abnormal hematopoiesis as well as gene therapy(ref).”

·        “Progressive telomere shortening limits stem cell divisions and probably acts as a tumor suppressor mechanism. Using a sensitive PCR method to detect the length of individual telomere repeats on specific chromosomes, we confirmed that telomere length decreases from primitive to more differentiated human cell types within the hematopoietic hierarchy(ref).”  

 2.     Telomere length regulation and telomere attrition are very complex matters involving many other factors besides the availability of telomerase.  

·        “The regulation of telomere length and telomerase activity is a complex and dynamic process that is tightly linked to cell cycle regulation in human stem cells(ref).”

·        “ Telomere length in peripheral blood mononuclear cells is associated with folate status in men. — Telomere length is epigenetically regulated by DNA methylation, which in turn could be modulated by folate status. — We propose that folate status influences telomere length by affecting DNA integrity and the epigenetic regulation of telomere length through DNA methylation(ref).”

·        “With aging, long telomeres decrease and short telomeres increase, and the contents of the telomeres with methylated subtelomere increase in long telomeres, thus leading us to postulate that telomeres with less methylated subtelomeres tend to become shortened faster.  —   The subtelomeric methylation of peripheral blood cells is also indicated to be an indicator for aging-associated genomic changes(ref).

See my treatise for more discussion of the complexities related to telomere lengths.  One study cited there showed that over a 9-11 year period, telomere lengths actually increased in about a third of 959 individuals as they aged.

3.     Disease conditions and cancers can lead to stem cell supply chain failures

·        “We have found heritable hypomorphic TERT mutations in other cancers as well, and we propose that such mutations result in short telomeres and premature loss of stem cells. Loss of normal stem cells could provide strong selection for abnormal cells incapable of responding to DNA damage signals originating from short telomeres(ref)”

4.     Genetic mutations in telomerase and shortened telomeres are implicated in a number of diseases.

·        “Genetic mutations in the components of telomerase (the RNA template sequence hTERC, reverse transcriptase hTERT, and Syskerin DKC1) have recently been implicated in a variety of bone marrow failure syndromes, idiopathic pulmonary fibrosis, and more recently, acute myeloid leukemia (AML)(ref).”

·        “The crucial role of telomeres in cell turnover and aging is highlighted by patients with 50% of normal telomerase levels resulting from a mutation in one of the telomerase genes. Short telomeres in such patients are implicated in a variety of disorders including dyskeratosis congenita, aplastic anemia, pulmonary fibrosis, and cancer(ref).”

·         “Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome characterized by cutaneous symptoms, including hyperpigmentation and nail dystrophy. Some forms of DC are caused by mutations in telomerase, the enzyme that counteracts telomere shortening, suggesting a telomere-based disease mechanism. — These results provide experimental support for the notion that DC is caused by telomere dysfunction, and demonstrate that key aspects of a human telomere-based disease can be modeled in the mouse(ref).”

·        “These results suggest that marrow failure in DC is caused by a reduction in the ability of hematopoietic stem cells to sustain their numbers due to telomere impairment rather than a qualitative defect in their commitment to specific lineages or in the ability of their lineage-restricted progeny to execute normal differentiation programs(ref).” Again, there is a direct link between the two theories of aging Stem Cell Supply Chain Breakdown and Telomere Shortening and Damage. 

·        ”Loss of (stem) cells via telomere attrition provides strong selection for abnormal cells in which malignant progression is facilitated by genome instability resulting from uncapped telomeres(ref).” 

·        “Inherited mutations in TERT that reduce telomerase activity are risk factors for acute myeloid leukemia. We propose that short and dysfunctional telomeres limit normal stem cell proliferation and predispose for leukemia by selection of stem cells with defective DNA damage responses that are prone to genome instability(ref).”

·        “Although we could not find a statistical difference in the mean telomere length of peripheral leukocytes between the PD (Parkinson’s Disease) patients and the control participants, we found the mean telomere lengths to be shorter than 5 kb in only the PD patients and a significant PD-associated decrease in the telomeres with a length ranging from 23.1 to 9.4 kb in the patients in their 50s and 60s. These observations suggest that telomere shortening is accelerated in PD patients in comparison to the normal population(ref).”  I note that telomere shortening is observed in many disease processes where the body’s response is speeding up cell division and differentiation, as may be the case in this instance.  Such a situation is different than one in which shortened or impaired telomeres are causative of the disease such as those described above.

·        “Studies in white people have shown that telomere length, a marker of biological ageing, is shorter in individuals with coronary artery disease (CAD). South Asian Indians have a high prevalence of CAD, especially premature CAD. — Subjects of Indian ethnicity with CAD have shorter telomeres than subjects without such a history. The finding provides further evidence that telomere biology is altered in subjects with CAD(ref).”

5.     Telomere attrition probably plays a key role in immunosenescence

·        “Macrophages from aged mice showed increased susceptibility to oxidants and an accumulation of intracellular reactive oxygen species. In these macrophages STAT5a oxidation was reduced, which led to the decreased phosphorylation observed. Interestingly, the same cellular defects were found in macrophages from telomerase knockout (Terc–/–) mice suggesting that telomere loss is the cause for the enhanced oxidative stress, the reduced Stat5a oxidation and phosphorylation and, ultimately, for the impaired GM-CSF-dependent macrophage proliferation(ref).

I upgraded the Telomere Shortening and Damage theory in my treatise on July 14 2009 and stand by what I said there.

Some of the above citations suggest how another of the theories of aging Susceptibility to Cancers integrates with the Stem Cell Supply Chain Breakdown and the Telomere Shortening and Damage theories.  And, I have argued that the Programmed Epigenomic Changes theory and the candidate Epigenomic Changes in DNA Methylation and Histone Acetylation theories of aging are completely compatible and complementary with the Stem Cell Supply Chain Breakdown theory.  We are in the process of converging on a unified systems model of aging.

On a personal note, for telomerase activation as soon as my current bottle of astragaloside IV is used up I will be switching to cycloastragenol as my primary telomerase-activating supplement, a new RevGenetics product.