Longevity Techniques: CR, Telomeres and More

Hereinafter, a few general  longevity and healing techniques that guide the Institute’s healing and longevity protocols. All of these show that going holistic, by activating endogenous longevity pathways tends, longevity is better achieved.

Caloric Restriction

The central proven (for the last 80 years) intervention that has been shown to significantly delay mammalian aging is caloric restriction (CR). Given the large body of research on CR, and the many products trying to emulate its effects, CR is one of the Institute’s Fundamentals. One of the key findings we have discovered is that CR is in reality less a restriction than proper eating. Most humans dont know how to eat according to their design, genome and instincts. As a consequence, they over-eat with too many calories. Once eating becomes holistic, the calories massively drop and the longevity genes get better expressed.

Hormonal Therapies

The levels of many hormones go down with age. Some of the oldest and still most popular anti-aging treatments are thus based on the notion that hormonal changes contribute to aging and reversing age-related hormonal changes will be beneficial. The most popular of these treatments involves human growth hormone (hGH) injections. Growth hormone has a long history as an anti-aging treatment and some evidence suggests hGH has beneficial effects in elderly people, in particular, regarding increased muscle mass, strengthen the immune system and increase libido. (1)

While hGH was once hailed as a major breakthrough, like many other anti-aging products it failed to live up to expectations, in part because of its negative side-effects. (2) These might include weight gain, high blood pressure, cancer promotion and diabetes. Because, as the name implies, hGH stimulates growth, concerns have also been raised as to whether hGH could stimulate cancer growth and whether it will contribute to cancer development in patients with existing malignant or pre-malignant tumors. Lots of animal studies have proven this. Many Medical Boards have removed the medical license of anti-aging doctors who practice this therapy (See Holistic Justice Institute website).

However activating human growth hormone holistically, from the inside has been shown to be beneficial (See Hormone dossier).

Insulin-like growth factor 1 (IGF-1) is another hormone that may play a role in aging and can be purchased as a supplement. IGF-1’s production is induced by GH and, like GH, IGF-1’s levels decline with age.  However, just like for hGH, IGF-1 injections can be counter-productive. In fact, there is  evidence that little people with low levels of IGF-1 live longer. (3)  However, a holistic harmonization of IGF-1 with hGH can be beneficial.

Other hormones whose production decreases with age include DHEA and melatonin. DHEA has been reported to improve the wellbeing of the elderly by a variety of ways: improved memory, immune system, muscle mass, sexual appetite, and benefits to the skin. Protection against cancer has also been argued but there is really no strong scientific evidence for this. Minor side effects such as acne have also been reported. One clinical study in elderly women found no evidence of benefits from DHEA. (4) On the other hand, when we put in place a holistic endogenous DHEA enhancement program, benefits abound.

Melatonin is a hormone mostly involved in sleep and circadian rhythms. It has been shown to also have antioxidant and good sleep functions. (5)  Some of its proponents claim it delays the aging process and many age-related diseases, though this is far from proven. In mice, melatonin can increase lifespan but also appears to increase cancer incidence. (6)

Although it can be used for jet lag and some sleep disorders, it may also cause sleep disorders such as nightmares and vivid dreams. It is the ACRI’s belief that melatonin levels do not decrease with age. It is because of drugs, medication and stress that the elderly have low melatonin.  (7)  Therefore, the endogenous and holistic production of melatonin is best.

Finally, for women, estrogen is a popular anti-aging therapy. This hormone is generally used in conjunction with others in hormone replacement therapy. It does appear to reduce some of the effects of menopause by protecting against heart disease and osteoporosis. On the other hand, it could increase risk of breast cancer and may lead to weight gain and thrombosis as side effects. There is a vast literature on the advantages and disadvantages of hormone replacement therapy. In the context of aging, there is no evidence that estrogen is a viable anti-aging therapy. For men, testosterone has also been touted as anti-aging but, again, there is no evidence it has anti-aging benefits even if it might have some benefits like, say, increased sexual function and muscle mass. (8) On the other hand, endogenous testosterone optimized via holistic savor-faire is a definite longevity booster.

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Antioxidants

One theory of aging is the free radical theory of aging. Succinctly, when oxygen is used to make energy in human cells, it releases reactive compounds called free radicals, also called reactive oxygen species (ROS). To fight ROS, cells possess an array of defenses called antioxidants, many of which can be synthesized or extracted, purified, and then sold, generally in tablets, as anti-aging drugs. Common antioxidants include vitamins A, C, and E and coenzyme Q10.

Unfortunately, there is little evidence any of these products actually work. In mice, for instance, many studies indicate that antioxidants do not slow aging. (9)  (Harman, 1968; Comfort et al., 1971; Heidrick et al., 1984; Holloszy, 1998; Saito et al., 1998). One large study found no evidence that multivitamin use influences mortality (Park et al., 2011).  (10)  A shorter lifespan due to antioxidant supplementation has also been observed in voles (Selman et al., 2013). (11) Overall, there is not enough good proof that antioxidants delay aging and some large-scale epidemiological studies even report that antioxidant supplements may actually increase mortality (Bjelakovic et al., 2007& 2008). (12)

Since one major source of ROS are mitochondria, a similar class of compounds are aimed at quenching ROS production in mitochondria. These can include not only antioxidants but products that allegedly “rejuvenate” mitochondria by optimizing metabolism or membrane potential. Like for many other products, however, none of these products has been proven to have any effect on aging, either in animal models or in humans. On the other hand, when we optimize anti-oxydant pathways holistically, the longevity and healing effects abound. Resveratrol and other red wine constituents can also act as antioxidants  and have been shown to protect the brain and other parts of the body. There is also some evidence that wine is good for longevity, though it should be organic and taken holistically. (13)

might be protective agents of brain aging (Tredici et al., 1999; Bastianetto and Quirion, 2002; Mokni et al., 2007).

Telomere-Based Therapies

Telomerase is an enzyme that, at least in some cell lines, appears to overcome cellular senescenceby extending the tips of the chromosomes called the telomeres–for more details please see another essay. Some have argued that if telomerase can avoid aging in cells in vitro, maybe it can be used to combat human aging (Fossel, 1996). A number of companies and labs are developing telomerase-based therapies to fight aging and at least one product, a natural product-derived telomerase activator called TA-65, is already available. One study reported that taking TA-65 may result in a decline of senescent immune system cells in patients (Harley et al., 2011). TA-65 can also increase telomerase levels in some mouse tissues and was reported to improve some health indicators in mice but it did not increase mean or maximum lifespan (de Jesus et al., 2011).

Even though our knowledge of telomerase is still imperfect, I am skeptical such therapies will succeed (de Magalhaes and Toussaint, 2004a). Firstly, as detailed elsewhere, mice expressing lots of telomerase do not live longer. Moreover, telomerase is important in cellular proliferation yet many of our organs, such as the brain, are mostly composed of cells that do not proliferate. Hence, telomerase will do little to alleviate aging in these tissues. Lastly, there is ample evidence telomerase favors tumorigenesis and so telomerase-based therapies may foster cancer development. Although research on telomerase is still in an early age, I have doubts about the efficiency and long-term safety of telomerase-based anti-aging therapies. The fact that TA-65 can increase telomerase levels but does not extend lifespan in mice (de Jesus et al., 2011) is in line with these thoughts. One high-profile study showed that telomerase reactivation reverses degeneration in mice (Jaskelioff et al., 2011). However, this study was conducted in animals that have no telomerase to begin with and thus develop a number of pathologies. Benefits from reactivating telomerase in mice that become sick for lack of telomerase are hardly surprising.

Some companies are also selling telomere measurements to estimate biological age. Although telomere shortening may be a marker of certain diseases, there is no evidence at present that telomere length is a better indicator of biological age than chronological age.

Stem Cells

In recent years stem cells have received widespread attention. This fame is partly merited given the huge potential of stem cells for regenerative medicine, as discussed elsewhere. The possibility of using stem cells to treat diseases of aging and for rejuvenation is also tantalizing. Having said that, and while depletion/dysfunction of stem cells are thought to play a role in aging (e.g., see de Magalhaes and Faragher, 2008), there is no evidence that stem cell-based anti-aging treatments will work. Harvesting and/or preparing stem cells for treatments is complex and much work remains to optimize protocols. In some areas indeed stem cells have been shown to be useful. For example, blood- and marrow-derived stem cells have been used successfully in some autoimmune and cardiovascular diseases (reviewed in Burt et al., 2008). Interestingly, mesenchymal stem cells transplanted from young donors extends lifespan in mice (Shen et al., 2011). Yet stem cell applications are still in their infancy and a long way before physicians can employ stem cells to delay aging.

ALT-711

ALT-711 is one of the latest anti-aging compounds to receive public attention. It acts by catalytically breaking AGE crosslinks: Advanced Glycosylation End-product crosslinks occur when glucose is attached to a protein, like it can happen in arteries. For this, ALT-711 seems to be useful against heart disease by reducing pulse pressure and improving arterial elasticity. The full effects and side-effects of this drug are still unknown but it seems like a promising intervention to ameliorate aging’s effects, though I remain skeptical–until proven contrary–that it can delay aging as a whole.

Future Therapies

One exciting finding in anti-aging research was the discovery that feeding rapamycin, also known as sirolimus, to middle-aged mice extends lifespan by 9-14% (Harrison et al., 2009). When fed to younger mice, rapamycin extend lifespan by 10-18% (Miller et al., 2011). In one small clinical trial rapamycin ameliorated immunosenescence in elderly volunteers (Mannick et al., 2014). Rapamycin is also an immunosuppressant, used to prevent organ rejection, with serious side-effects and so it is not suitable as an anti-aging drug. However, rapamycin works by inhibiting a complex pathway called TOR (Target of Rapamycin) and a number of labs and companies are now trying to target more specific downstream nodes of the pathway to develop anti-aging drugs without the side-effects of rapamycin (reviewed in de Magalhaes et al., 2012).

One gene that appears to influence aging in mice is klotho. As detailed elsewhere, high levels of klotho increase lifespan by about 30%, though it is not entirely clear if aging is delayed, and low levels appear to foster aging (Kuro-o et al., 1997). Human longevity has also been linked to allelic variants in this gene (Arking et al., 2002). Its functions are still largely a mystery but since the gene encodes one secreted form that acts as a hormone, it could be synthesized and presented as an anti-aging therapy. For now, however, we will just have to wait and see. There are many other aging-associated genesthat hold promise for pharmaceutical intervention, and progress has been made in finding chemicals that can modulate specific aging-associated genesand thus extend lifespan (Ja et al., 2007), as also debated elsewhere. On average, however, it takes 12 years from discovery of molecular mechanisms to develop a drug, plus 10 years of tests to make a drug available. In the case of aging the timescale may be longer, though many companies trying to develop anti-aging products are focusing on specific age-related diseases as a way to overcome the legal barriers of a product targeting aging (de Magalhaes et al., 2012& 2017).

Tentative Conclusions

There is no magic pill at present that will retard aging. But that is not to say there are not simple lifestyle and dietary adjustments that can make you live longer. Most components of a healthy lifestyle are well-known already, and I will be just stating the obvious. Still, a varied, rich diet with plenty of fruits and vegetables and low in carbohydrates and fat is likely to make you live longer. As an example, look at the Okinawan population in Japan in which older individuals have a lower risk of age-related chronic diseases and mortality when compared to the rest of Japan. Okinawans tend to avoid high calories sugars, saturated fats and processed foods and instead consume more vegetables and fruits, which has likely contribute to their long lifespan (Willcox et al., 2006). Conversely, smoking, excess alcohol, obesity, lack of exercise and high blood pressure are all associated with higher mortality. One study showed that middle aged (45-64 years of age) people who adopted a healthy lifestyle by consuming five or more fruits and vegetables daily, regular exercise, healthy body mass index (BMI) (18.5-29.9 kg/m2) and not smoking experienced a prompt benefit in lower rates of cardiovascular disease and mortality (King et al., 2007). Clearly, not smoking, exercise, moderate wine intake and fruit and vegetable intake are associated with lower mortality (Khaw et al., 2008).

Reference

(1) Blackman M. R., Sorkin, J. D., Munzer, T., Bellantoni, M. F., Busby-Whitehead, J., Stevens, T. E., Jayme, J., O’Connor, K. G., Christmas, C., Tobin, J. D., et al.(2002). “Growth hormone and sex steroid administration in healthysaged women and men: a randomized controlled trial.” Jama288(18):2282-2292. PubMed

Liu, H., Bravata, D. M., Olkin, I., Nayak, S., Roberts, B., Garber, A. M., and Hoffman, A. R. (2007). “Systematic review: the safety and efficacy of growth hormone in the healthy elderly.” Ann Intern Med146(2):104-115. PubMed

Khansari, D. N., and Gustad, T. (1991). “Effects of long-term, low-dose growth hormone therapy on immune function and life expectancy of mice.” Mech Ageing Dev57(1):87-100. PubMed

Nair, K. S., Rizza, R. A., O’Brien, P., Dhatariya, K., Short, K. R., Nehra, A., Vittone, J. L., Klee, G. G., Basu, A., Basu, R., et al.(2006). “DHEA in elderly women and DHEA or testosterone in elderly men.” N Engl J Med355(16):1647-1659. PubMed

(5). Poeggeler, B. (2005). “Melatonin, aging, and age-related diseases: perspectives for prevention, intervention, and therapy.” Endocrine27(2):201-212. PubMed

(6). Anisimov, V. N., Zavarzina, N. Y., Zabezhinski, M. A., Popovich, I. G., Zimina, O. A., Shtylick, A. V., Arutjunyan, A. V., Oparina, T. I., Prokopenko, V. M., Mikhalski, A. I., et al.(2001). “Melatonin increases both life span and tumor incidence in female CBA mice.” J Gerontol A Biol Sci Med Sci56(7):B311-323. PubMed

Zhao, Z. Y., Xie, Y., Fu, Y. R., Bogdan, A., and Touitou, Y. (2002). “Aging and the circadian rhythm of melatonin: a cross-sectional study of Chinese subjects 30-110 yr of age.” Chronobiol Int19(6):1171-1182. PubMed

Dominguez, L. J., Barbagallo, M., and Morley, J. E. (2009). “Anti-aging medicine: pitfalls and hopes.” Aging Male12(1):13-20. PubMed

 

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