Slowing Telomere Attrition and Cellular Senescence—Today: Part I

Abstract

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.

Introduction

Cellular Senescence, Not the Hayflick Limit, Key to Aging

Although cellular senescence is one of the body’s protective mechanisms against cancer, it plays a key pathological role in other age-associated diseases and in so-called “healthy aging.” Until recently, the increase in cellular senescence seen with aging has been attributed to 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, alterations that result in inadequate responses to free radicals and free radical damage. And the degradation that triggers these alterations occurs in most somatic cells well before they reach replicative senescence, the inborn replicative limit at which division potential is lost (often referred to as the “Hayflick limit” in deference to Hayflick and Moorhead’s discovery of it in 1961).¹

Telomere Attrition, Key to Cellular Senescence

Some cell types, i.e., cancer cells and germ cells, are able to supersede the Hayflick limit’s barrier to continued cellular renewal. In addition, certain stem cell lines (including hematopoietic stem cells, gastrointestinal crypt cells, hair follicles, and possibly liver cells), that do experience replicative senescence, do so only after a much larger number of cellular divisions than typically seen in somatic cells.

The extended life span characteristic of all these cell types derives from their ability to maintain the protective caps at the ends of their chromosomes, called telomeres (from the Greek telos [end], and meros [part]). By securing the ends of chromosomes, telomeres reduce nucleolytic degradation and end-to-end ligation, protecting cells’ genomic integrity and stability.

Telomeres shorten with each round of DNA replication, until sufficient numbers have been lost to trigger the changes in gene expression that result in the abrogation of repair and maintenance mechanisms, and cause the cell to enter senescence and irreversible growth arrest. Telomere shortening, not the “wear and tear” of oxidative damage, is the proximate activator of the cellular switch for replicative senescence. In turn, it is replicative senescence that underlies the systemic process of aging in the organism since even non-dividing cells depend on cells that divide, and cellular senescence occurs well before the Hayflick limit has been reached.{ref1,{ref2,{ref3,{ref4,⁵

Tomorrow’s Strategies to Prevent Telomere Attrition

Research investigating the anti-aging potential of telomere manipulation has focused on telomerase, an enzyme comprised of a reverse transcriptase containing an RNA template and a catalytic protein that adds DNA bases to telomeres, thus continually renewing telomere length. Recent studies have demonstrated that inserting a gene for the protein component of telomerase into senescent human skin cells (fibroblasts and keratinocytes) restores their telomeres to lengths typical of young cells, and these cells then revert to the gene expression pattern and phenotype of young, healthy cells. Not only does telomere restoration not cause cancer in these cells, which remain normal in all respects except that they do not age, it appears to make them more resistant to DNA damage and malignant transformation.{ref1,{ref6,{ref7,⁸

Although telomere restoration has been successfully accomplished in human cells via insertion of a new telomerase reverse transcriptase (hTERT) gene, resulting in telomerase expression and activity, this process remains many years away from practical use as an anti-aging therapy for humans. Renowned neurobiologist, researcher, and author of Cells, Aging and Human Disease, Michael Fossel, PhD., MD., is a strong advocate of the promise of telomerase therapy as an effective treatment for progeria and other accelerated aging syndromes, and as an anti-aging intervention in general, but even he believes the first human clinical trials remain a decade away.⁹

Today’s Strategies that Slow Telomere Attrition

Fortunately, a rapidly growing body of research is revealing that leukocyte telomere dynamics (leukocyte telomere length and age-dependent attrition rate, a well accepted biological indicator of human aging), can be directly affected by environmental and lifestyle factors, many of which we can impact right now.¹⁰

The rate at which normal somatic cells divide (and therefore the rate at which telomeres shorten) is significantly upregulated by:

• Vitamin D insufficiency
• Exposure to avoidable toxins, e.g., cigarette smoke
• Menopausal decline in estrogen
• Oxidative stress due to mitochondrial dysfunction
• Psychological stress
• Chronic diseases highly correlated with avoidable diet and lifestyle choices, e.g., type 2 diabetes, hypertension, hypercholesterolemia, HIV/AIDS

Therapeutic Strategies to Decrease Telomere Attrition Today

Check Vitamin D Levels and Supplement if Needed: Vitamin D Adequacy is Associated with Increased Telomere Length

Leukocyte telomere length (LTL) is a well accepted predictor of aging-related disease. Specifically, decreased leukocyte telomere length (LTL) has been shown to be highly associated with osteoblast senescence, decreased bone mineral density (BMD) and osteoporosis.¹¹

British researchers examined the relationship between LTL, BMD and osteoporosis in a cohort of 2,150 women from a population-based twin cohort aged 18-79. After adjusting for age, body mass index, menopausal status, smoking, and hormone replacement therapy status, telomere length positively correlated with BMD of the spine and forearm, and longer telomeres were associated with reduced the risk of clinical osteoporosis. In women >50, clinical osteoporosis was associated with shorter telomere length of 117 base pairs, the equivalent of 5.2 years of telomeric aging.¹²

LTL decreases with each cell cycle, and increased inflammation is known to increase the rate of cell cycling. The same British researchers hypothesized that vitamin D, a potent inhibitor of the pro-inflammatory response, would diminish leukocyte turnover, thus slowing the rate of telomere attrition in leukocytes. When they measured serum vitamin D concentrations in 2,160 women aged 18-79 (mean age 49.4) from the same population-based twin cohort, vitamin D concentrations were strongly negatively associated with both C-reactive protein, a key measure of systemic inflammation, and LTL, a relationship that persisted after adjustment for age, season of vitamin D measurement, menopausal status, use of hormone replacement therapy, and physical activity. Lower vitamin D levels directly correlated with increased concentrations of C-reactive protein and shortened LTL. The difference in LTL between the highest and lowest tertiles of vitamin D was 107 base pairs—the equivalent to 5 years of telomeric aging.¹³

Consider Bio-identical HRT: Estrogen Lessens Oxidative Stress and Activates Telomerase

Estrogen is linked to leukocyte telomere dynamics through both its anti-inflammatory and antioxidant effects and its ability to stimulate telomerase. A potent anti-inflammatory agent, estrogen lowers the production of pro-inflammatory cytokines, including TNFα, and also defends against oxidative stress by stimulating mitochondrial superoxide dismutase and glutathione peroxidase, two key enzymes that neutralize reactive oxygen species.

In addition, the catalytic subunit of telomerase, TERT, possesses an estrogen response element. Estrogen stimulates telomerase via TERT and through other posttranscriptional modifications that include Akt protein kinase, a downstream mediator of phosphoinositol-3-kinase (PI3K). Estrogen stimulates the PI3K/Akt cascade and induces the Akt-dependent endothelial nitric-oxide synthase to increase nitric oxide production and stimulate telomerase activity.¹⁴

A retrospective case control study investigated the influence of long-term hormone therapy (HT) on telomere length in 130 postmenopausal women from 55 to 69 years of age. The women were divided into two groups: the HT group included 65 women who had been on estrogen and progesterone therapy for more than five years, and the non-HT group, composed of 65 women matched in age to the HT group who had never had HT. Relative telomere length ratios in the HT group were significantly greater than those in the non-HT group, even after control for potential confounding variables (lipid profiles, total antioxidant status, CRP, fasting glucose levels, estradiol levels, age at menopause, vitamin use, exercise, alcohol and cigarette smoking).¹⁵

Synthetic HRT, however, has been definitively associated with increased inflammation and risk of cardiovascular disease and breast cancer. Landmark studies, including the Heart and Estrogen/Progestin Replacement Study (HERS) and Women’s Health Initiative (WHI), provide strong evidence that synthetic HRT (estrogen/progestin replacement) can produce detrimental effects on coagulative balance and vascular inflammation, and increases coronary artery risk in postmenopausal women.^{16 17} In addition, synthetic HRT, regardless of whether estrogen is given alone or combined with progestin, increases the risk of ischemic stroke by 40%.¹⁸

These research findings are cause for legitimate concern; however, when considering HRT, it is critical to note that the compounds used in synthetic HRT have neither the same chemical structure nor the same pharmacokinetic behavior as the bio-identical hormones, estradiol 17beta and progesterone, and the latter not only have not been found to confer the increased cardiovascular and cancer risks associated with synthetic HRT, but to lessen inflammation.^{19 20}

Read Part II: Slowing Telomere Attrition and Cellular Senescence—Today

References