Commentary: This study supports two potential conclusions: 1. Age reversal in mammals is possible, and 2. The mechanism of action to do so is via expression of the telomerase enzyme. A lot more could be written about this study, but those two points are a lot to digest themselves.

 

Commentary: As we discuss in “Why blaming telomerase for cancer is misguided and counterproductive“, short telomeres increase cancer risk. From the paper:

“Telomeres are essential to preserve the integrity of the genome. Critically short telomeres lead to replicative cell senescence and chromosomal instability and may thereby increase cancer risk.” The study authors conclude: “Short telomere length at baseline was associated with incident cancer independently of standard cancer risk factors. […] In this study population, there was a statistically significant inverse relationship between telomere length and both cancer incidence and mortality.”

 

Commentary: This study essentially identifies the location of the hTERT (telomerase) gene to chromosome 5p15.33 in the human genome. The focus on this study was oriented toward cancer research.

 

Commentary: Supports the argument that CDKs are an important contributor to cancer. From the paper: “A variety of genetic and epigenetic events cause universal overactivity of the cell cycle cdks in human cancer, and their inhibition can lead to both cell cycle arrest and apoptosis.”

 

Commentary: From the paper: “Tumour-associated cell cycle defects are often mediated by alterations in cyclin-dependent kinase (CDK) activity. Misregulated CDKs induce unscheduled proliferation as well as genomic and chromosomal instability.” In other words, defects in or misregulation of CDKs can lead to excessive cell proliferation and cancer.

 

Commentary: Great summary of many of the concepts of cellular senescence and how it relates to both pathologies and aging. From the paper: “[I]n the past, research into mechanisms of ageing has commonly been researched and treated separately from disease development. This may partly be due to the lack of understanding concerning mechanisms of ageing and the difficulty in implementing what was known into models of disease development. Only in the last 10 years, with increasing knowledge of the senescent phenotype and the ability to detect senescent cells in human tissues, have biologists been able to investigate the relationship between cellular senescence and disease. This review therefore brings together and discusses recent findings which suggest that cellular senescence does contribute to ageing and the development/progression of disease.” […]

“Both ageing and disease result in the same outcome: the impairment of normal biological function. It would not, therefore, be a surprise if tissue dysfunction resulting from an ageing mechanism eventually manifested itself as a disease. Therefore, understanding mechanisms of ageing would help understand the processes which govern the development and progression of some diseases. This in turn would lead to the development of new therapeutic methods for disease treatment and, more importantly, prevention.” […]

“Telomerase therapy is aimed at preventing the appearance of senescent cells by elongating the telomeres of somatic cells. The idea is to develop strategies for transiently turning on telomerase in cells. This results in longer telomeres, a higher replicative capacity and a reduced chance of a cell becoming senescent through replication.”

 

Commentary: From the paper: “The relationship between short telomere length and ageing or disease states in various cells of the body is increasingly reported. Paradoxically, the introduction of telomerase is proposed as a method to combat ageing via cell therapy and a possible method to regenerate tissue, while telomerase inhibition and telomere shortening is suggested as a possible therapy to defeat cancers […].”

 

 

Commentary: In a study of twins, shorter telomere length in immune cells correlated with an earlier mortality.

 

10. Contributions of Telomere Biology to Human Age-Related Disease
Handbook of the Biology of Aging (Eighth Edition) 2016, Pages 205-239.
Ting-Lin B.Yang, Shufei Song, F. Brad Johnson
https://www.sciencedirect.com/science/article/pii/B9780124115965000071
Commentary: The authors review the evidence regarding the relationship between short telomeres and pathologies of aging, including cardiovascular diseases, cancer, osteoporosis, menopause, type 2 diabetes mellitus, pulmonary fibrosis, and cirrhosis. The authors conclude that short telomeres do play a key role in many of the pathologies evaluated.

 

Commentary: Provides a lot of great background information about telomere biology, and also summarizes some of the data from existing research literature related to telomere biology and several age-related pathologies.

 

 

 

 

15. Mutations in the p53 Tumor Suppressor Gene: Clues to Cancer Etiology and Molecular Pathogenesist
Cancer Research 54, 4855-4878, September 5, 1994
M. S. Greenblatt, W. P. Bennett, M. Hollstein, and C. C. Harris
http://cancerres.aacrjournals.org/content/54/18/4855
https://pdfs.semanticscholar.org/20bc/1b2e03520f5c25108ed4a98ad543f2c0bcbc.pdf
Commentary: Supports the hypothesis that mutations of the p53 gene plays a key role in the formation of many cancers.

 

16. p21 in cancer: intricate networks and multiple activities
Nature Reviews Cancer volume 9, pages 400–414, 2009
Tarek Abbas, Anindya Dutta
https://www.nature.com/articles/nrc2657
Commentary: Supports the hypothesis that mutations of the p21 gene also plays a key role in the formation of many cancers.

 

 

The article “Rethinking Telomeres” in The Scientist magazine provides a more approachable summary of the study above.

 

 

Commentary: An in vitro proof of concept of fibroblast (skin cell) regeneration by telomerase.

 

Commentary:Dyskeratosis congenita (DKC) is characterized by an absence of functional telomerase and short telomeres. Yet despite the lack of functional telomerase, people with this disorder are much more prone to developing cancer than the general population, which is counter to the “conventional” paradigm regarding telomerase.

 

Commentary: A good summary of the relationship between telomeres, telomerase, and mitochondrial function.

 

Commentary: Elaborates on the relationship between telomeres and mitochondrial function. Considers implications for cardiovascular disease.

 

Commentary: “In embryonic stem cells, telomerase is activated and maintains telomere length and cellular immortality; however, 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.”

 

Commentary: Provides evidence that induced Pluripotent Stem Cells (iPSCs) do express telomerase. Upregulating telomerase production seems to be a necessary step in creating iPSC cells. This raises the interesting possibility that iPSCs may one day also be a useful life extension therapy to replace senescent stem cells. However our compounds can upregulate telomerase production in cells now.

 

Commentary: Provides more evidence that induced Pluripotent Stem Cells (iPSCs) do express telomerase. Upregulating telomerase production seems to be a necessary step in creating iPSC cells. This raises the interesting possibility that iPSCs may one day also be a useful life extension therapy to replace senescent stem cells. However our compounds can upregulate telomerase production in cells now.

 

Commentary: The pathology of aging is multi-factoral. While telomerase therapies play a necessary key role in addressing age-dependent pathologies, they will likely not be sufficient. However we will not know with any certainty which aspects of aging will be ameliorated in vivo by telomerase therapies until in vivo trials are performed. We believe that at least five of the eight aspects of aging mentioned will be either fully corrected or dramatically improved by telomerase therapy. These are: telomere attrition, cellular senescence, stem cell exhaustion, genomic instability, and some aspects of mitochondrial dysfunction.

 

Commentary: One of several studies that connect Hutchinson-Gilford Progeria Syndrome (HGPS) to greatly accelerated telomere attrition.

 

Commentary: A proposed model of causation and for treatment of Hutchinson-Gilford Progeria Syndrome (HGPS), and what implications it may have for other age related diseases.

 

Commentary: “In this study, we have shown in normal human fibroblasts that progressive telomere damage during cellular senescence plays a causative role in activating progerin production. […] Interestingly, elevated progerin production was not seen during cellular senescence that does not entail telomere shortening.”

The accepted model of Progeria is that the mutant form of Lamin A adversely affects the shape, integrity and function of the nuclear membrane. However we believe that part of the adverse affects of such compromised nuclear membranes is to accelerate telomere attrition. And that the accelerated telomere loss contributes to many of the observed pathologies seen in progeria.

 

Commentary: “We demonstrate that telomerase extends HGPS cellular lifespan by decreasing progerin-induced DNA-damage signaling and activation of p53 and Rb pathways that otherwise mediate the onset of premature senescence. We show further that progerin-induced DNA-damage signaling is localized to telomeres and is associated with telomere aggregates and chromosomal aberrations.”

 

Commentary: This study demonstrates several important proof of concepts, as follows. First, that telomerase therapies do not increase cancer risk. Second, that telomerase therapies improve many markers and pathologies of aging. Third, that telomerase therapies increase maximal life span and “health span”. However, as we explain in one of our FAQs, there are some issues that need to be overcome for AAV gene therapies to become realistic for clinical application. These issues include high cost, target effectiveness in a sufficiently large population of cells, regulatory approval (due to unknown safety parameters), and (in)convenience of an IV therapy.

 

 

Commentary: Reviews the evidence of how senescent cells can have deleterious effects in tissue. Explains the concept Senescence-Associated Secretory Phenotype (SASP). “[R]ecent studies show that senescent cells develop altered secretory activities that may induce changes in the tissue microenvironment, relaxing its control over cell behavior and promoting tumorigenesis.” […] “A plethora of stresses can provoke cellular senescence. These stresses include telomeric dysfunction (telomere uncapping) resulting from repeated cell division (termed replicative senescence), mitochondrial deterioration, oxidative stress, severe or irreparable DNA damage and chromatin disruption (genotoxic stress), and the expression of certain oncogenes (oncogene-induced senescence).”

 

Commentary: “Importantly, mice with hyper-long telomeres show an increased longevity and develop less tumors associated with aging. Together, these findings demonstrate that longer telomeres than normal show beneficial effects in mice, delaying metabolic aging and cancer, and resulting in longer lifespans.” […] “We found that hyper-long telomere mice showed a reduction of almost 50% in the number of mice that developed tumors compared to the normal telomere length control mice”. This result regarding decreased incidence of tumors correlates with our own in vitro research with human fibroblast cells. When we treat human fibroblast cells with TeloMore, we find a reduced rate of cancerous transformation compared to controls. Again, this leads us to argue that the “conventional view” of telomerase needs to change. “[…] there is mounting evidence that telomerase re-activation in the adult organism by using non-integrative gene adeno associated vectors (AAV) does not lead to increased cancer, even in the context of activated oncogenes, in mice^44,45,46,47.”