Prevalence of Telomerase in Coronary Artery Atherosclerosis

Summary: Telomerase detected in atherosclerotic plaque tissue, likely to be related to restenosis.

Interestingness: 3

Paper by Madhu Gupta, Marie R Shogreen, Gregory A Braden, Wain L White and David C Sane in the Journal of Anti-Aging Medicine, Volume 3, Issue 1, Spring 2000.


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They measured the presence of telomerase in the bits cut out of 23 people that had directional coronary atherectomy (DCA). The bits cut out are blockages of the coronary artery and the DCA cuts it out. They correlated the tissues in which they detected telomerase with those that had restenosis, which is when the blockage/narrowing of the artery reappears.

They detected telomerase in 8 out of the 23 total, in 5 out of the 7 people who later developed restenosis, and on 2 out of the 10 who didn't (p < 0.05). Results were inconclusive for restenosis in the other 6. There was no correlation between what the people had come in for and the presence of telomerase.

They mention that atherosclerotic plaques have a monoclonal population of smooth muscle cells, but I don't know what other type you could have inside one person. They offer three explanations for the 35% detection rate of telomerase, that is, how come it's not 100%:

• that the tissue is maintaining its telomeres by means other than telomeres
• that the tissue is senescent or closer to senescence, with some evidence coming from studies on replicative capacity of muscle cells from plaque-derived tissue compared to healthy arteries. The presence of telomerase would probably be induced by cells having replicated beyond the normal senescent stage by a viral infection or broken tumor-suppressors, and that this would activate telomerase. These cells would then be better able to cause restenosis. I have no idea how much reality there is to that idea of telomerase reactivation.
• that there was no telomerase in the smooth-muscle cells at all, and instead the telomerase was detected from other cells in the tissue cut out. This could be from vascular stem cells, or from non-related cells like endothelial cells, lymphocytes or macrophages.

They also mention that the telomerase could be driving the hyperplasia not by replication but by stopping apoptosis.

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Abstract follows:

Telomerase is an essential enzyme for maintaining the telomeres of chromosomes and thereby enhancing the sustained replication of cells. Because atherosclerosis and restenosis are characterized by cellular proliferation, we determined whether telomerase enzyme activity was present in coronary artery tissue from 23 patients undergoing directional coronary atherectomy. Telomerase activity was determined from detergent lysates of the atherectomy tissue using an enzyme-linked immunoadsorbent assay (ELISA)-based modification of the Telomere Repeat Amplification Protocol. The presence of telomerase activity was correlated with the occurrence of coronary artery restenosis. Eight of the 23 samples (35%) were positive for telomerase. Seventeen of the 23 patients had adequate clinical follow-up to judge restenosis status. Of these, 7 had restenosis and 5 of these 7 had detectable telomerase. Of the 10 patients without restenosis, 8 were telomerase negative (p <= 0.05). We have shown, for the first time, that telomerase is found in 35% of atherosclerotic tissues. There was a strong trend toward an association between telomerase presence and restenosis in patients for whom follow-up data were available. The presence of telomerase in atherosclerotic tissue may enable a robust, sustained cellular proliferation in response to vascular injury that culminates in restenosis.

Rest of volume 2, Issue 4

The rest of issue 4 of 1999 consists of:

A review of a book called Essentials of Clinical Geriatrics, 4th edition, edited by Robert L Kane, Joseph G Ouslander and
Itamar B Abrass. "Concise" 621 pages of differences between geriatric and standard medicine.


Seven article reviews by L Stephen Coles:

• Gene expression profile of aging and its retardation by caloric restriction, by Cheoi-Koo Lee, Roger G Klopp, Richard Weindruch and Tomas A Prolla, in Science. Analysis of what genes change in muscle cells in old mice compared to young mice compared to old calorie restricted mice using a gene chip of 6000 genes. Lots of changes, with caloric restriction reducing the changes by 84%. L Stephen Coles thought this was a very important paper.
  
• Can human aging be postponed?, by Michael R Rose, in Scientific American. Some pop-sci sounding piece.
• Designer genomes, by Karen Hopkin, in Scientific American. Another pop-sci sounding piece about creating cells from scratch. Mentions Venter's knock out method of finding the minimal set. I didn't know he had been going at it that long.
• Telomeres and telomerase in cancer, by Christopher M Counter, in Science and Medicine. Supposedly nice graphics.
• Aging: The price of evolutionary success, by Robert F Rosenberger, in Science Spectra: The international magazine of contemporary scientific thought. About germ vs soma.
• The hunt for the youth pill: From cell-immortalizing drugs to cloned organs, biotech finds new ways to fight against time's toll, by David Stipp, in Fortune Magazine.
• Never say die, by Lisa Leff, in the Los Angeles Magazine.

Season of Birth and Human Longevity

Summary: Adult women over thirty live three years longer if they were born in May or December, rather than in August.

Interestingness: 2

Paper by Leonid A Gavrilov and Natalia S Gavrilova in the Journal of Anti-Aging Medicine, Volume 2, Issue 4, Winter 1999.

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Short two-page paper analysing a subset of the same data they used for their longevity vs fertility paper, ie European aristocratic families. In this case, they analysed a lot of variables until they found one that correlated with longevity.

On the relevant subsample of 4911 women, adult women over 30 born between 1800 and 1880 lived shortest if they were born in August and longest if they were born in May with the difference at about three and a half years. This is after correcting for a whole heap of variables that have nothing to do with month of birth but are related to longevity: year of birth, maternal and paternal life spans, age of parents at birth, birth order, nationality, whether the death was violent, loss of either or both parents before age twenty.

They have a graph and it doesn't look good to me. The only reasons I can think of, and that they propose, for the effect would be availability of vitamins (or calories but they are unlikely to be a problem for this group since they were all from aristocratic families) at specific points in the pregnancy or early life, but the graph is very noisy and it mostly jumps up and down. For example, the difference between July and August births is two and a bit years, and between August and September the difference is about a year and a half, with August at the minimum. The other bad months are February and March, on the other side of the year, with women born then living about a year longer than those in August. If the effect is real, then the critical periods during pregnancy must be very short.

I'm not buying any of it until it gets replicated.
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Adaptive Response to Swimming Exercise: Antioxidant Systems and Lipid Peroxidation

Summary: Anti-oxidant enzyme concentrations go up in the blood of rats that go swimming

Interestingness: 1

Paper by M Cesquini, MA Torsoni and SH Ogo in the Journal of Anti-Aging Medicine, Volume 2, Issue 4, Winter 1999.

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The abstract has everything covered. Note that these tests were on three groups of four rats each. Also, catalase was down on the endurance-trained group.
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Abstract follows:

Enzymatic and nonenzymatic antioxidants play an essential role in protecting tissues from oxidative damage during exercise. The present study investigated the levels of glutathione and antioxidant enzyme systems in the blood of unexercised and exercised (one bout of exhaustive swimming and adapted to swimming endurance training) rats. The hemoglobin concentration, hematocrit, and extent of oxidative injury to red blood cell (RBC) membranes were examined in the above groups of rats. The concentration of reduced glutathione (GSH) in the blood of exercised rats was about 30% higher than in the resting controls (0.40 Å [±] 0.12 GSH/Hb tetramer). Glutathione peroxidase (1.83 Å 0.24 X 102 IU/g Hb), glutathione reductase (1.73 Å 0.44 IU/g Hb), and Superoxide dismutase activities were significantly higher in both groups of exercised rats, whereas catalase activity (8.32 Å 1.04 X 104 IU/g Hb) was similar in the exercised and control animals. The hemoglobin concentration (11.8 g Hb/dL) and hematocrit (39.4%) increased with swimming exercise. Although lipid peroxidation is known to occur following physical exercise, the increased activity of the antioxidant enzymes and cell GSH levels in the present study were able to prevent lipid peroxidation of the RBC membrane. As a result, there was no significant variation in the plasma malondialdehyde levels among the three groups of rats. The redox capacity of the blood may have an important role in the organism in general since the redox status can be transferred across the RBC plasma membrane to other tissues. Exercise training is therefore beneficial to general health and protects cells against deleterious effects of reactive oxygen species produced during physical effort.

Pycnogenol Improves Learning Impairment and Memory Deficit in Senescence-Accelerated Mice

Summary: Senescence accelerated mice of the memory-impairment variety do better learning with pycnogenol.

Interestingness: 2

Paper by Fujun Liu, Yongxiang Zhang and Benjamin HS Lau in the Journal of Anti-Aging Medicine, Volume 2, Issue 4, Winter 1999.

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This is another one of those give substance to senescence accelerated mice (SAM) (see http://readingrejuvenationresearch.blogspot.com/2010/01/interventions-of-senescence-in-sam-mice.html), watch them act normal type papers. In this case, the substance, pycnogenol, was a commercial extract of the bark of the French maritime pine, which is made up mostly of procyanidins, which is the class of oligomers of flavonoids. The SAM chosen was SAMP8, which has mental issues. The task was learning. The SAMP8 did better when given the substance compared to controls, and about as well as the SAM resistant variety in these groups of 10 mice each. The suspected mechanism is anti-oxidant activity. Whoopee.

The interesting bit of the paper is the description of the memory experiments, which I'd heard mentioned before, as passive and active avoidance, but not described.

The passive avoidance tests are the if-you-move-I-shoot type, and they did two tests, called step-through and step-down. In the step-through test, mice are put in a bright area. There is a little tunnel to go to the dark area. Mice usually try to avoid being in a bright area, but when they go through the tunnel they get electrically shocked. If they don't go through on subsequent tests, it is assumed that they learnt. In the step-down test, they are put on a small rubber pad, surrounded by a sea of electric shock metallic mesh. If they stay on the pad for ten minutes, they "win".

The active avoidance test is, as expected, approximately the opposite. They are put in an area with two infrared beams that can be triggered. For ten seconds before the mesh below their feet becomes electrified, an alarm sounds and a light goes on, then the electricity is turned on for ten seconds. If they trigger both beams while the alarm is going on, either before or during the electric shock, the electricity is turned off. To trigger the beams they would have to run around.
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Abstract follows:

Pycnogenol (procyanidins extracted from the bark of French maritime pine, Pinus maritima Aiton) has been shown to be a potent free radical scavenger and an antioxidant phytochemical. The effects of pycnogenol on learning impairment and memory deficit in senescence-accelerated mouse (SAM) as a murine model of accelerated aging were determined. SAMP8, a strain of senescence-prone mice, exhibits immunodeficiency, hemopoietic dysfunction, learning impairment, and memory deficit. The effects of pycnogenol on learning performance and memory deficit were measured using step-through and step-down passive avoidance tests and shuttle box conditioned avoidance test. Oral feeding with pycnogenol for 2 months increased the retention rate in the step-through and the step-down tests and the rate of conditioned avoidance response in the shuttle box test. The latency of mice in the step-through test and the number of successful mice in the step-down test also increased with pycnogenol feeding. These results suggest that pycnogenol can improve learning impairment and memory deficit associated with aging.

Thyrotropin-Releasing Hormone Accelerates and Enhances the Age-Postponing Effects of Melatonin

Summary: Thyrotropin-releasing hormone (TRH) plus melatonin increase lifespan of old mice by three months

Interestingness: 4

Paper by Walter Pierpaoli, Daniele Bulian, Gordana Bulian and Gonzague Kistler in the Journal of Anti-Aging Medicine, Volume 2, Issue 4, Winter 1999.

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The sample size is small, 15 mice per group, but the effect size is interesting. The main table of results shows the following: for four groups of 15+-1 BALB/cJ female mice, 20 months old at the start of the experiment, a control group, one given melatonin, one TRH, one both, mean survival was 765+-54 days, 810+-50 days, 804+-80 days, and 861+-70 days respectively. There's also other results, with the TRH plus melatonin combination raising numbers of leukocytes and blood lymphocytes, and lowering cholesterol and triglycerides in old mice.

TRH induces release of thyrotropin, aka thyroid-stimulating hormone (TSH) which then induces the thyroid to release T3 and T4. Wikipedia has TRH being produced in the hypothalamus but the paper says it's produced by the hypothalamus and the pineal gland.

The mechanism behind this isn't precisely hypothesised but they do mention immune system upregulation. The authors hype TRH as the real reason for the supposed effects of melatonin on aging, saying that melatonin dosing stops the pineal gland making its own, so it can stay young and keep on making TRH later. TRH is also given as the explanation of why pineal gland transplantation from young to old mice, mentioned in http://readingrejuvenationresearch.blogspot.com/2010/03/perspective-on-proposed-association-of.html, increases the longevity of those mice.

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Abstract follows:

Studies over a period of several years have suggested an age-postponing effect of circadian nocturnal administration of melatonin and of young-to-old pineal grafting in rodents. Of the two procedures, the effect of pineal grafting was significantly more pronounced. Also, old-to-young and young-to-old pineal transplantation in normal or pinealectomized recipients suggested that the pineal itself contains the capacity to prevent or to accelerate the course of aging depending on the age of the donor and/or of a recipient when the pineal is transplanted. This observation prompted the idea that the "program of aging" might be governed by the capacity of the pineal to maintain the control of central neuroendocrine functions and to constantly synchronize the synthesis and release of hormones according to a strict circadian periodicity and seasonal rhythmicity. This report deals with the experimental evidence that, while melatonin alone exerts a low-level age-postponing activity, its age-delaying effects are greatly enhanced and accelerated when given in combination with a pineal peptide, thyrotropin-releasing hormone (TRH). This peptide may be a key element in the mechanism by which both melatonin and pineal grafting might postpone aging. In fact, as suggested by our data here, TRH could be one of the basic mediators in the brain (pineal-hypothalamic-hypophyseal axis) and in peripheral endocrine glands (e.g., the beta, insulin-producing cells in the pancreas). TRH may directly translate the light and temperature-mediated environmental stimuli into rapid energy-adapting biochemical processes which constantly monitor cell functions relating to energy production, in particular those required for thermoregulation. We show here that this energy-monitoring action of TRH is not thyroid mediated. We also show that TRH is not itself a toxic agent even when administered daily for long periods at a very high pharmacological dosage.

Effect of Carnosine on Age-Induced Changes in Senescence-Accelerated Mice

Summary: Carnosine extends median survival on an accelerated-aging model of mice by about 20%

Interestingness: 2

Paper by MO Yuneva, ER Bulygina, SC Gallant, GG Kramarenko, SL Stvolinsky, ML Semyonova and AA Boldyrev in the Journal of Anti-Aging Medicine, Volume 2, Issue 4, Winter 1999.

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In a study of two groups of 70 senescence-accelerated mice prone 1 (SAMP1) each, carnosine extended the time taken until half the mice in its group died. That is, on a plot of age versus percentage of animals alive, plotting both SAMP1 control and SAMP1 given carnosine groups, both curves start at 100% and drop to zero%. They reach zero at around the same age (17 months), but the control curve drops earlier, with the 50% mark being around 10 months for control and 12 months for the carnosine'd mice. Other benefits included glossier fur, less skin ulcers, and much more reactivity and passive avoidance. I don't know what reactivity is, but was in the group with passive avoidance. From wikipedia, I get that carnosine raises corticosterone. Doesn't sound good to me.

SAMP1 mice are whacked though, so again, I don't put much weight on this. SAMP1 mice are prone to amyloidoisis (http://readingrejuvenationresearch.blogspot.com/2010/01/interventions-of-senescence-in-sam-mice.html).

They don't know about the mechanism of action. They suggest a few: carnosine is a oxide radical scavenger, it prevents radical production in the first place, and it is an antiglycation agent, but maybe something else.

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Abstract follows:

The effect of carnosine on the life span and several brain biochemical characteristics in senescence-accelerated mice-prone 1 (SAMP1) was investigated. A 50% survival rate of animals treated with carnosine increased by 20% as compared to controls. Moreover, the number of animals that lived to an old age significantly increased. The effect of carnosine on life span was accompanied by a decrease in the level of 2'-tiobarbituric acid reactive substances (TBARS), monoamine oxidase b (MAO b), and Na/K-ATPase activity. There was also an increase in glutamate binding to N-methyl-D-aspartate receptors. These observations are consistent with the conclusion that carnosine increases life span and quality of life by diminishing production of lipid peroxides and reducing the influence of reactive oxygen species (ROS) on membrane proteins.