From the Methods section of Robin JD et al:CD56-positive myoblasts from primary muscle biopsies were infected with retroviral constructs containing CDK4 and a floxable
human TERT as described (Stadler et al. 2013). Individual clones were then treated with Cre-recombinase at different times and cultivated for approximately the same number
of population doublings to generate isogenic subclones with different telomere lengths….supports telomere shortening as a cause of aging.
retroviral-infected myoblasts …. regulate aging ?
Am I correct to conclude that the neuroendocrine system plays an insignificant role in human aging?
On Sun, Mar 22, 2015 at 10:09 AM, Stanley Primmer wrote:
A recent study by Jerry Shay, Woodring (“Woody”) Wright, and colleagues supports telomere shortening as a cause of aging. The abstract at http://ift.tt/1LL2MUa follows.
Genes Dev. 2014 Nov 15;28(22):2464-76. doi: 10.1101/gad.251041.114.
Telomere position effect: regulation of gene expression with progressive telomere shortening over long distances.
Robin JD1, Ludlow AT1, Batten K1, Magdinier F2, Stadler G1, Wagner KR3, Shay JW4, Wright WE1.
1Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
2UMRS 910, INSERM, Aix Marseille University, Marseille 13385 Cedex 05 France;
3Center for Genetic Muscle Disorders, Kennedy Krieger Institute, Baltimore, Maryland 21205, USA; Department of Neurology, Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA;
4Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; Center for Excellence in Genomics Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia email@example.com.
While global chromatin conformation studies are emerging, very little is known about the chromatin conformation of human telomeres. Most studies have focused on the role of telomeres as a tumor suppressor mechanism. Here we describe how telomere length regulates gene expression long before telomeres become short enough to produce a DNA damage response (senescence). We directly mapped the interactions adjacent to specific telomere ends using a Hi-C (chromosome capture followed by high-throughput sequencing) technique modified to enrich for specific genomic regions. We demonstrate that chromosome looping brings the telomere close to genes up to 10 Mb away from the telomere when telomeres are long and that the same loci become separated when telomeres are short. Furthermore, expression array analysis reveals that many loci, including noncoding RNAs, may be regulated by telomere length. We report three genes (ISG15 [interferon-stimulated gene 15 kd], DSP [Desmoplakin], and C1S [complement component 1s subcomplement]) located at three different subtelomeric ends (1p, 6p, and 12p) whose expressions are altered with telomere length. Additionally, we confirmed by in situ analysis (3D-FISH [three-dimensional fluorescence in situ hybridization]) that chromosomal looping occurs between the loci of those genes and their respective telomere ends. We term this process TPE-OLD for “telomere position effect over long distances.” Our results suggest a potential novel mechanism for how telomere shortening could contribute to aging and disease initiation/progression in human cells long before the induction of a critical DNA damage response.
© 2014 Robin et al.; Published by Cold Spring Harbor Laboratory Press.
TA-65 and Product B are known mild activators of telomerase. Two years ago I asked Woody Wright if he took TA-65. His response was, “ABSOLUTELY NOT.” He didn’t shout, but he was very emphatic. Not long after I asked Jerry Shay the same question. He said that TA-65 had been offered to him for free but that he declined the offer. The opposition to activating telomerase is the fear that it would increase the risk for cancer. In conversations with Roger Reddel, Utz Herbig, and Anthony Cesare, they all agreed. Maria Blasco’s study with mice found no increase in cancer as a result of activating telomerase. The theory is that if cells are precancerous due to multiple mutations that do not activate telomerase, activation of telomerase by exogenous means will increase the pool of cells that could become fully cancerous. The statistical likelihood of having more cells on the verge of becoming cancerous would increase the risk. I recognized this potential several years ago, but telomerase also has anticancer effects. Because available products are only mild activators of telomerase, I think the risk is minimal compared to the rewards. Therefore, I took TA-65 for about 4 years. It was ineffective for me in maintaining my telomeres, so I switched to Product B. I haven’t had my telomeres measured yet since switching, so I don’t know if it is effective. Other products are available that claim to activate telomerase, but I have no information about their effectiveness. A question I have is whether the alleged risk of cancer is only theoretical or if there are studies to support or invalidate the theory. I haven’t completed my study of the literature to be sure what the answer is.
Those interested in learning about the latest research in telomere biology may want to attend the Telomeres and Telomerase conference at Cold Spring Harbor Laboratory from Apr. 28 to May 2, 2015. See http://ift.tt/1LL2Pzt for details. I will be there.
From: firstname.lastname@example.org [mailto:email@example.com] On Behalf Of firstname.lastname@example.orgSent: Sunday, March 22, 2015 6:25 AMTo: Thomas Coote; Josh MitteldorfCc: Gerontology Research GroupSubject: Re: [GRG] are short telomeres a cause or a result of aging?
I would not say they are the only cause of aging but short telomeres certainly contribute. Short telomeres encourage gene expression that promotes inflammation and senescence not only in themselves but in adjacent cells via sasp.
Longer telomeres offer protection and encourage youthful gene expression via the tpe effect aka telomere positioning effect.
Longer telomeres promote a similar level of youthful expression via tpe over long distances aka tpe-old. Almost like the reverse of sasp and how it influences nearby cells.
Short telomeres are not the sole driver of aging but i believe they are acting not only as a cell division clock but also as a gene expression regulator that determines what genes to express based on its length. In other words it’s length tells it how old it should be and this influences the age of its local environment. This also may explain how some organs age faster in some people than others, some local telomere populations are wearing out sooner than others likely due to more exposure to stressors.
If you reset telomere length you should see restoration of tissue and I believe a return to youthful gene expression. This restoration has been observed in animal studies eg, blasco et al.
I believe telomeres are contributing to aging via gene expression. They are not the only cause of aging but they are one of them which makes them a primary driver of aging as they cause so much damage when they shorten.
Big reason they should be targeted as a priority