Slowing Telomere Attrition and Cellular Senescence—Today: Part II
Cellular senescence, although protective when triggered in cells that have become cancerous, plays a key pathological role in other age-associated diseases and in so-called "healthy aging." The age-associated increase in cellular senescence has been assumed to result from the cumulative effects of "wear and tear," but genetic research has revealed that cellular senescence occurs only when cells permit it by altering their gene expression to down-regulate repair mechanisms. Aging occurs not because our genes lose their capacity to restore health, but because of alterations in patterns of gene expression that result in inadequate responses to oxidative damage. These alterations are triggered by the loss of the protective caps at the ends of chromosomes called telomeres, which occurs with each round of DNA replication. Telomere shortening, not the "wear and tear" of oxidative damage, is the proximate activator of the cellular switch for replicative senescence. Research investigating the anti-aging potential of telomere manipulation has focused on the insertion of a new gene for telomerase, the enzyme that renews telomeres, but this strategy may increase oncogenic risk and remains at least a decade away from clinical use. Fortunately, a rapidly growing body of research is revealing that telomere length and attrition rate can be directly affected by environmental and lifestyle factors, which we can impact right now. This article reviews the research on these modifiable factors, which have been shown to significantly attenuate telomere attrition.
Consider Supplementation to Support Mitochondrial Function--Oxidative Stress Accelerates Telomere Attrition1
While telomere loss is the proximate cause of cellular senescence since it triggers a halt in cellular mechanisms to repair oxidative damage, oxidative stress plays a key secondary role by greatly accelerating the rate of telomere attrition in mature individuals.
In rats, telomere loss follows a pattern of heightened attrition in the rapid growth period in early life, during which the body is growing quickly by means of rapid cell division; a long stable period until adulthood; and then gradual attrition, largely due to oxidative damage, later in life. A similar pattern of telomere shortening occurs in humans. Telomere repeats are lost very rapidly from peripheral blood leukocytes in young children, followed by an apparent plateau between the age of 4 and adulthood, and then gradual attrition later in life, at a rate significantly impacted by the amount of oxidative stress to which adult cells are subjected.
Recent studies indicate that telomeres “score” the amount of oxidative damage to which our cells are exposed. Telomeric DNA sequences, especially their characteristic GGG triplet repeat sequence, are a major target for reactive oxygen species. In experiments in which a human telomere insert and a similar-sized control fragment were exposed to hydrogen peroxide in the presence of iron and ethanol, the telomere insert acquired sevenfold more strand breakage than the control.
In vitro experiments in replicating fibroblasts have demonstrated that oxidative stress, exerted by mild hyperoxia, accelerates the rate of aging by causing telomere loss. (In addition to its effects on telomeres, oxidative stress-induced DNA strand breaks also trigger the p53-dependent cell cycle exit pathway, which mediates the senescent inhibition of cellular replication.)
In other research, the suppression of intracellular oxidative stress by an oxidation-resistant type of ascorbic acid has been shown to decrease the rate of age-dependent telomere shortening by 52–62% and significantly extend cellular life-span in human vascular endothelial cells compared to untreated controls.
A relationship between oxidative damage and telomere attrition has also been noted in vivo in human respiratory chain disorders, in which increased production of reactive oxygen species is a well-recognized factor. Leukocyte telomeres in patients with LHON (Leber hereditary optic neuropathy), and MELAS (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes)-related mitochondriopathies have been found to be an average 1.5 kilobases shorter than those of age-matched controls.
Mitochondrial dysfunction plays key role in oxidative stress and telomere shortening
Oxidative stress shortens telomeres.2 3 4 5 6 Oxidative stress and accumulating reactive oxygen species (ROS) lead to an increased rate of telomere shortening due to a less efficient repair of single strand breaks in telomeres themselves, i.e., in the specialized structures of telomeres, which include proteins involved in both telomere maintenance and DNA repair.7
Not only do the data consistently show that telomere shortening rates are dependent on oxidative stress levels, and that mitochondrial dysfunction can accelerate telomere shortening, but also that improvement in mitochondrial function lowers the production of ROS and lessens telomere attrition.2 3
Supplementation with nutrients necessary for efficient mitochondrial energy production minimizes ROS generation and telomere attrition. Key mitochondrial nutrients include: vitamin C, vitamin E (mixed tocopherols and tocotrienols), thiamin, riboflavin, magnesium, creatine, N-acetyl cysteine, lipoic acid, acetyl-L-carnitine, and coenzyme Q10.8 9 10 11
Prescribe Exercise: Regular Physical Activity is Associated with Longer Telomeres
A sedentary lifestyle increases telomere attrition and may accelerate the aging process. Researchers evaluated 2,401 white twin volunteers (2,152 women and 249 men), using questionnaires on physical activity level, smoking status, and socioeconomic status, and checking leukocyte telomere length (LTL), which was adjusted for age and other potential confounders. LTL was significantly positively associated with increasing physical activity in leisure time, an association that remained significant after adjustment for age, sex, body mass index, smoking, socioeconomic status, and physical activity at work.
LTLs of the most active subjects were 200 nucleotides longer than those of the least active subjects (7.1 and 6.9 kilobases [kb], respectively), and this finding was confirmed in a small group of twin pairs in whom, on average, the LTL of more active twins was 88 nucleotides longer than that of less active twins.12
High intensity exercise is, however, known to increase oxidative stress. In other research, investigators looked at whether the increase in malondialdehyde (a marker of oxidative stress) typically seen immediately post-exercise, would correlate with a negative effect on telomere length in obese, middle-aged women. It did not. Six months of mid- and high-intensity aerobic exercise training resulted in decreased body weight and BMI, increased VO2 max, and higher levels of endogenous antioxidants (glutathione peroxidase and superoxide dismutase), with no reduction in telomere length.13
One More Reason Your Patients Should Quit: Smoking Significantly Decreases Telomere Length
A clear dose-dependent relationship has been noted between smoking and white blood cells (WBC) telomere length in two large population studies. Each pack-year smoked corresponds to a statistically significant decrease in WBC telomere length—yet another way in which smoking accelerates aging.14 15
Other reports indicate a greater-than-additive interaction between smoking status and telomere length. WBC telomere lengths have been found to be shorter in individuals with smoking-related head and neck, lung, renal, and bladder cancer than in other individuals with these cancers.16 17 Additional studies suggest the inverse correlation between smoking and telomere length may be a significant environmental factor inducing breast cancer in women with breast cancer onset under age 40.18
Provide Stress Reduction Counseling: Chronic Psychological Stress Shortens TelomeresError! Bookmark not defined.
Chronic psychological stress is associated with shorter telomeres. Women with both perceived stress and actual chronic stress have significantly lower white blood cell (WBC) telomerase activity and shorter telomeres.19 In one study, women with the highest level of perceived stress had telomere lengths equivalent to the lowest perceived stress level group who were ten years older. In another study conducted by the same researchers, telomere shortening and lower telomerase activity in white blood cells were associated with stress arousal as measured by nocturnal stress hormones.20
Recent in vitro research has revealed a potential mechanism for stress-associated telomere length attrition: exposure to cortisol greatly reduces telomerase activity in human T lymphocytes.21 Effective stress reduction options include biofeedback, massage, spirituality/meditation/religious practice.
Phosphatidylserine may also be helpful. Researchers investigated the effects of phosphatidylserine (PS) supplementation on pituitary adrenal reactivity (ACTH, cortisol) and on the psychological response (Spielberger State Anxiety Inventory stress subscale) to a mental and emotional stressor. Four groups of 20 subjects were treated for three weeks with PS in daily doses of either 400 mg, 600 mg 800 mg, or placebo, before exposure to the Trier Social Stress Test (TSST). Interestingly, treatment with 400 mg PS, but not larger doses, resulted in a pronounced blunting of both serum ACTH and cortisol, and salivary cortisol responses to the TSST. The 400 mg dose of PS also seemed to exert a specific positive effect on emotional responses to the TSST. While the placebo group showed the expected increase in distress after the test, the group treated with 400 mg PS showed decreased distress.22
Practice Safe Sex: HIV Infection Increases Telomere Attrition
Provide Nutrition Counseling for Patients with Cardiovascular Disease and Diabetes—Both Increase Telomere Attrition
Shortening of telomere length has been reported in several conditions including atherosclerosis, hypertension, insulin resistance/metabolic syndrome and type 2 diabetes. In all these conditions, incidence highly correlates with inappropriate dietary choices, i.e., the calorie-dense, nutrient-poor, pro-inflammatory Standard American Diet (for which the acronym is, appropriately, SAD).
Cardiovascular Disease Associated with Telomere Shortening
A number of recent studies have shown that leukocytes of patients with atherosclerosis and heart failure display remarkably shorter telomeres compared to leukocytes of healthy subjects of similar age.25 26
Researchers measured telomere length in 686 male US World War II and Korean War veteran twins ranging in age from 73-85 years. The sample set was selected for pairs in which one or more co-twins were free of cardiovascular disease. Telomere length was largely associated with shared environmental factors. No evidence of heritable effects on telomere length maintenance was seen. Men with hypertension (a major risk factor for cardiovascular disease) or cardiovascular disease had significantly shorter telomeres than their co-twins.27 28 29
In other research involving 327 men (mean age 62.2 years) from the Offspring cohort of the Framingham Heart Study, leukocyte telomere length was inversely correlated with hypertension, and shorter leukocyte telomere length in hypertensives was found to be largely due to insulin resistance.30
Even Pre-Diabetes (Impaired Glucose Tolerance) Increases Telomere Loss
A number of recent studies have confirmed a significant correlation between type 2 diabetes and telomere attrition.31 32 Now research indicates that this relationship is progressive. Deleterious effects occur in the early, "pre-diabetes" stage of impaired glucose tolerance, with the rate of attrition increasing as the severity of metabolic dysfunction increases. Subjects with type 2 diabetes show a higher rate of telomere loss than those with impaired glucose tolerance, and subjects with type 2 diabetes with atherosclerotic plaques show greater telomere attrition compared to those without plaques.
Indian investigators compared subjects with impaired glucose tolerance (n=30), type 2 diabetic patients without (n=30) and with atherosclerotic plaques (n=30), and healthy controls (n=30), selected from the Chennai Urban Rural Epidemiology Study (CURES), an ongoing epidemiological population-based study.33 Leukocyte telomere length, levels of thiobarbituric acid reactive substances (TBARS, a measure of lipid peroxidation, which form during the decomposition of lipid peroxidation products and react with thiobarbituric acid to form a fluorescent red adduct), protein carbonyl content (PCO, a marker of protein oxidation, which forms earlier and is more stable than lipid peroxidation products34, high sensitivity C-reactive protein (hsCRP, a marker of inflammation), and carotid intima-media thickness (IMT, a marker of the progression of arteriosclerosis) were assessed.
Compared to controls, in whom telomere length averaged 8.7kb, telomere length was an average 6.97kb in subjects with impaired glucose tolerance; shorter still in subjects with type 2 diabetes without atherosclerotic plaques (average of 6.21); and shortest in subjects with type 2 diabetes with atherosclerotic plaques (average of 5.39).
In subjects with impaired glucose tolerance, telomere length positively correlated to HDL cholesterol and negatively correlated to glycated hemoglobin (HbA1c), TBARS, PCO, and IMT.
Diet and Key Nutritional Supplements: Effective Therapy to Prevent Telomere Attrition Today
Evidence assembled over the last decade clearly shows that average telomere length acts as a biomarker for biological aging, and that shorter telomere length is associated with an increasingly unhealthy lifestyle.
Belgian researchers measured leukocyte telomere length in a large, representative Asklepios study cohort (2,509 community-dwelling, Caucasian female and male volunteers aged 35-55 years and free of overt cardiovascular disease). They found age-dependent telomere attrition, at a significantly faster rate in men as compared to women, and that leukocyte telomere length primarily reflects the burden of increased oxidative stress and inflammation, which, in turn, is largely determined by diet and lifestyle.35
In contrast, positive lifestyle interventions have been repeatedly and strongly associated with longer telomeres. Many studies have shown that healthy diet and lifestyle patterns markedly reduce cardiometabolic risk, positively affecting metabolic syndrome, and the rate of progression of type 2 diabetes and cardiovascular diseases, while other studies have shown that oral diabetes drugs considered together (acarbose, metformin, flumamine, glipizide, phenformin) are less effective than lifestyle interventions.36
In one just published dietary intervention study, 49 subjects with metabolic syndrome and hypercholesterolemia, aged 25-80, were divided into 2 groups. One group ate a Mediterranean-style low-glycemic index diet (MED), while the other group (PED) followed the same diet enhanced with phytochemicals shown to increase insulin sensitivity (specifically, soy protein, phytosterols, and phytonutrients from hops [rho iso-alpha acid] and acacia.) Both groups followed the same aerobic exercise program.
Both groups experienced equal weight loss (MED: -5.7 kg; PED: -5.9 kg). However, at 12 weeks, the PED arm experienced greater reductions in cholesterol, non-HDL cholesterol, triglycerides, cholesterol/HDL and triglycerides/HDL compared with the MED arm. Furthermore, HDL cholesterol increased only in the PED arm, which also experienced a decrease in the ratio of triglycerides:HDL, and continued reduction in apo B/apo A-I from 8 to 12 weeks. Furthermore, 43% of PED subjects vs. only 22% of MED subjects had net resolution of metabolic syndrome. The Framingham 10-year CVD risk score decreased by 5.6% in the PED arm and 2.9% in the MED arm.37
As noted above, higher levels of HDL correlate with longer telomere length. In addition to a Mediterranean-style diet, dietary interventions as simple as a daily 8-ounce glass of cranberry juice or daily consumption of 3 ounces (100 grams) of probiotic yogurt have been shown to increase HDL levels.
In the research on cranberry juice, 30 abdominally obese men, averaging 51 years in age, drank increasing amounts (4 ounces, 8 ounces and 12 ounces daily) of low-calorie cranberry juice during three successive 4-week periods. No changes in the men's HDL were noted after drinking 4 ounces of cranberry juice each day, but a large increase (+8.6%) in circulating levels of HDL was seen after the men drank 8-ounces of cranberry juice daily, an effect that leveled out (+8.1%) during the final 12-ounce phase of the study. When drinking 8 ounces of cranberry juice daily, the men's triglyceride levels also dropped, while their levels of total and LDL cholesterol remained unchanged—a significant improvement in overall lipid profile. Study authors hypothesize cranberries' polyphenolic compouds are responsible for these very beneficial effects.38 The researchers selected abdominally obese men for this trial since abdominal obesity, high triglycerides, and being male, have been strongly linked to low HDL and cardiovascular disease.39
Women were the subjects of the research on yogurt. In this study, one group of 17 women consumed 3 ounces (100 g) a day of probiotic yogurt, while a second group of 16 women were given 3 ounces of conventional yogurt daily for 2 weeks. Then both groups were given 6 ounces (200 g) of the type of yogurt they had been consuming for 2 more weeks. The study ended with a final 2 weeks during which both groups of women ate no yogurt. In the women consuming probiotic yogurt, not only did LDL levels decrease significantly, but HDL levels substantially increased. Women consuming conventional yogurt also experienced a significant drop in LDL cholesterol, although their HDL did not rise.40
Mechanistically, probiotic bacteria ferment food-derived indigestible carbohydrates to produce short-chain fatty acids in the gut, which can then cause a decrease in the systemic levels of blood lipids by inhibiting hepatic cholesterol synthesis and/or redistributing cholesterol from plasma to the liver. Some bacteria may also interfere with cholesterol absorption from the gut by deconjugating bile salts or by directly assimilating cholesterol. Some pre-biotic yogurts are also fortified the nutrients supportive of probiotic bacteria, namely, the fructooligosaccharides, inulin and oligofructose. For these prebiotic substances, two studies conducted in normal-lipidemic subjects have reported a significant reduction in serum triglycerides (19 and 27%, respectively) with modest decreases in serum total and LDL cholesterol. At present, the research suggests that in hyperlipidemic subjects, yogurt consumption's primary benefit is to reduce cholesterol, whereas in normal lipidemic subjects, effects on serum triglycerides are the dominant benefit.41
The rate of telomere attrition is significantly affected by diet and lifestyle choices. A growing body of research supports the clinical effectiveness of a whole foods, low glycemic index/glycemic load, Mediterranean-style diet enhanced by supplementation with key nutrients to minimize oxidative stress and inflammation, and thus, telomere attrition. We do not have to wait ten years to see if genetic manipulation of telomerase can be developed into clinically relevant therapy. Your clinical judgment and guidance in developing a diet, exercise and supplement program individualized to address your patients' specific needs can have an immediate and long-reaching impact on their ability to maintain telomere length and longevity.
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Passos JF, von Zglinicki T. Mitochondria, telomeres and cell senescence. Exp Gerontol. 2005 Jun;40(6):466-72. ↑
Passos JF, Saretzki G, von Zglinicki T. DNA damage in telomeres and mitochondria during cellular senescence: is there a connection?. Nucleic Acids Res. 2007;35(22):7505-13. ↑
Liu L,Trimarchi JR, Smith PJ, et al. Mitochondrial dysfunction leads to telomere attrition and genomic instability. Aging Cell. 1 (2002), pp. 40–46. ↑
K. Oexle and A. Zwirner. Advanced telomere shortening in respiratory chain disorders. Hum. Mol. Genet. Hum. Mol. Genet. ↑
von Zglinicki T. Oxidative stress shortens telomeres. Trends Biochem Sci. 27 (2002), pp. 339–344. ↑
Ayouaz A, Raynaud C, Heride C, et al. Telomeres: hallmarks of radiosensitivity. Biochimie. 008 Jan;90(1):60-72. ↑
Miquel J, Ramírez-Boscá A, Ramírez-Bosca JV, et al. Menopause: a review on the role of oxygen stress and favorable effects of dietary antioxidants. Arch Gerontol Geriatr. 2006 May-Jun;42(3):289-306. ↑
Liu J, Ames BN. Reducing mitochondrial decay with mitochondrial nutrients to delay and treat cognitive dysfunction, Alzheimer's disease, and Parkinson's disease. Nutr Neurosci. 2005 Apr;8(2):67-89. ↑
Liu J. The effects and mechanisms of mitochondrial nutrient alpha-lipoic acid on improving age-associated mitochondrial and cognitive dysfunction: an overview. Neurochem Res. 2008 Jan;33(1):194-203. ↑
Miquel J. Can antioxidant diet supplementation protect against age-related mitochondrial damage?. Ann N Y Acad Sci. 2002 Apr;959:508-16. ↑
Cherkas LF, Hunkin JL, Kato BS, et al. The association between physical activity in leisure time and leukocyte telomere length. Arch Intern Med. Arch Intern Med. ↑
Shin YA, Lee JH, Song W, et al. Exercise training improves the antioxidant enzyme activity with no changes of telomere length. Mech Ageing Dev. 2008 May;129(5):254-60. ↑
Valdes A, Andrew T, Gardner J, et al. Obesity, cigarette smoking, and telomere length in women. Lancet. 2005 366, 662–664. ↑
McGrath M,Wong J, Michaud D, et al. Telomere length, cigarette smoking, and bladder cancer risk in men and women. Cancer Epidemiol. Biomarkers Prev. 2007 16, 815–819. ↑
Wu X, Amos C, Zhu Y, et al. Telomere dysfunction: a potential cancer predisposition factor. . Natl. Cancer Inst. 2003 95, 1211–1218. ↑
McGrath M,Wong J, Michaud D, et al. Telomere length, cigarette smoking, and bladder cancer risk in men and women. Cancer Epidemiol. Biomarkers Prev. 2007 16, 815–819. ↑
Yankaskas B. Epidemiology of breast cancer in young women. Breast Dis. 2005–2006 23, 3–8. ↑
Choi J, Fauce SR, Effros RB. Reduced telomerase activity in human T lymphocytes exposed to cortisol. Brain Behav Immun. 2008 May;22(4):600-5. ↑
Epel E, Blackburn E, Lin J, et al. Accelerated telomere shortening in response to life stress. Proc. Natl. Acad. Sci. U.S.A. 101, 17312–17315. ↑
Epel E, Lin J., Wilhelm F, et al. Cell aging in relation to stress arousal and cardiovascular disease risk. Psychoneuroendocrinology. 2006 Apr;31(3):277-87. ↑
Hellhammer J, Fries E, Buss C, et al. Effects of soy lecithin phosphatidic acid and phosphatidylserine complex (PAS) on the endocrine and psychological responses to mental stress. Stress. 2004 Jun;7(2):119-26. ↑
Dagarag M, Evazyan T, Rao N, et al. Genetic manipulation of telomerase in HIV-specific CD8+ T cells: enhanced antiviral functions accompany the increased proliferative potential and telomere length stabilization. J. Immunol. 2004 173, 6303–6311. ↑
Franzese O, Adamo R, Pollicita M, et al. Telomerase activity, hTERT expression, and phosphorylation are downregulated in CD4(+) T lymphocytes infected with human immunodeficiency virus type 1 (HIV-1). J. Med. Virol. 2007 79, 639– 646. ↑
Huzen J, van Veldhuisen DJ, van Gilst WH, et al. Telomeres and biological ageing in cardiovascular disease. Ned Tijdschr Geneeskd. 2008 May 31;152(22):1265-70. ↑
van der Harst P, van der Steege G, de Boer RA, et al. Telomere length of circulating leukocytes is decreased in patients with chronic heart failure. J Am Coll Cardiol. 2007 Apr 3;49(13):1459-64. ↑
Samani N, Boultby R, Butler R, et al. Telomere shortening in atherosclerosis. Lancet . 2001; 358, 472–473. ↑
Serrano A, Andres V. Telomeres and cardiovascular disease: does size matter? . Circ. Res. 2004; 94, 575–584. ↑
Huda N, Tanaka H, Herbert BS, et al. Shared environmental factors associated with telomere length maintenance in elderly male twins. Aging Cell. 2007; Oct;6(5):709-13. ↑
Demissie S, Levy D, Benjamin EJ, et al. nsulin resistance, oxidative stress, hypertension, and leukocyte telomere length in men from the Framingham Heart Study. Aging Cell. 2006 Aug;5(4):325-30. ↑
Tentolouris N, Nzietchueng R, Cattan V, et al. White blood cells telomere length is shorter in males with type 2 diabetes and microalbuminuria. Diabetes Care. 2007 Nov;30(11):2909-15. ↑
Sampson MJ, Winterbone MS, Hughes JC, et al. Monocyte telomere shortening and oxidative DNA damage in type 2 diabetes. Diabetes Care. 2006 Feb;29(2):283-9. ↑
Adaikalakoteswari A, Balasubramanyam M, Ravikumar R, et al. Association of telomere shortening with impaired glucose tolerance and diabetic macroangiopathy. Atherosclerosis. 2007 Nov;195(1):83-9. ↑
Mutlu-Türkoğlu U, Akalin Z, Ilhan E,, et al. Increased plasma malondialdehyde and protein carbonyl levels and lymphocyte DNA damage in patients with angiographically defined coronary artery disease. Clin Biochem. 2005 Dec;38(12):1059-65. ↑
Bekaert S, De Meyer T, Rietzschel ER, et al. Telomere length and cardiovascular risk factors in a middle-aged population free of overt cardiovascular disease. Aging Cell. 2007 Oct;6(5):639-47. ↑
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Lerman RH, Minich DM, Darland G, et al. Enhancement of a modified Mediterranean-style, low glycemic load diet with specific phytochemicals improves cardiometabolic risk factors in subjects with metabolic syndrome and hypercholesterolemia in. Nutr Metab (Lond). 2008 Nov 4;5(1):29. [Epub ahead of print]. ↑
Ruel G., Omperleau S, et al.) Ruel G, Pomerleau S, Couture P, Lemieux S, Lamarche B, Couillard C. . Favourable impact of low-calorie cranberry juice consumption on plasma HDL-cholesterol concentrations in men. Br J Nutr. 2006 Aug;96(2):357-64. ↑
Farnier M, Garnier P, Yau C, Dejager S, Verpilleux MP. Prevalence of low HDL-cholesterol in patients with cardiovascular risk factors: The ECHOS (Etude du Cholesterol HDL en Observationnel) French Survey. Int J Clin Pract. 2006 Oct;60(10):1166-71. Epub 2006 Aug 24. ↑
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Lara Pizzorno is a member of the American Medical Writers Association with 25+ years of experience writing for physicians and the public, Lara is Editor for Longevity Medicine Review as well as Senior Medical Editor for SaluGenecists, Inc. Read more...
Lara Pizzorno, MDiv, MA, LMT
John Morgenthaler has been active in the field of nutritional medicine since 1986. Today, John travels the world looking for breakthrough nutraceuticals and anti-aging therapies. He also continues to publish cutting-edge nutrition and medical science books and periodicals. Read more...
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