Super-Longevity Protocol: General Principles



Caloric Restriction

The only known intervention that might be able to delay human aging is caloric restriction (CR). Given the large body of research on CR, and the many products trying to emulate its effects, CR is discussed in its own essay.

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 famous 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 (e.g., see Blackman et al., 2002): hGH supplements might increase muscle mass, strengthen the immune system and increase libido. There are studies in elderly patients in which they claim to feel younger after hGH treatment. 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 (Liu et al., 2007). These might include weight gain, high blood pressure 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.

Studies in mice do not by and large suggest a beneficial role for GH. If any, they suggest a harmful role. Though one study found that a low-dose GH therapy increases lifespan in aged mice (Khansari and Gustad, 1991), mice genetically modified to produce lots of GH live less than controls while mice producing less GH live longer (Coschigano et al., 2000; Laron, 2005). Of course, as mentioned above, studies in animals are not always relevant to human biology. Nonetheless, the results in mice suggest that higher GH levels will not make you live longer. Studies in humans with a deficiency in GH signalling due to a defect in the GH receptor also suggest a strong cancer protection due to decreased GH signalling (Guevara-Aguirre et al., 2011). The human studies also hint at a sort of supernova effect: hGH makes patients feel better but might actually diminish their lifespan. In conclusion, hGH might be useful in certain aged patients, for example its use has been suggested in cases of depression, but by and large it should be seen as cocaine for granddad. Lastly, I should point out that there are (young) patients with GH deficiency that if untreated have a reduced longevity (Besson et al., 2003), so hGH does have clinical applications.

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 and, in mice, low levels of IGF-1 appear to correlate with longevity; mutations in mice that lower IGF-1 seem to extend lifespan, as detailed elsewhere. So, just like for hGH, IGF-1 injections could be counter-productive. In fact, there is some evidence that little people with low levels of IGF-1 live longer (Krzisnik et al., 1999). Interestingly, anti-aging therapies based on lowering IGF-1 may be possible (Miller, 2005). As mentioned elsewhere, IGF-1 does appear to play a role in aging, but whether it can be used in anti-aging is pure speculation at this stage. Clearly, however, IGF-1 injections are unlikely to extend lifespan and, like hGH, may even be harmful.

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 (Nair et al., 2006).

Melatonin is a hormone mostly involved in sleep and circadian rhythms, the latter hypothesized by some to be associated with aging and life-extension (Froy and Miskin, 2007; Kondratov, 2007). It appears to have antioxidant functions–more about antioxidants below–in the brain and may have some beneficial effects in elderly patients in particular in terms of sleep (Poeggeler, 2005). 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 (Anisimov et al., 2001). In humans there is no data to determine whether melatonin extends longevity, though it might have benefits in some patients (Karasek, 2004). Although it can be used for jet lag and some sleep disorders, it may also cause sleep disorders such as nightmares and vivid dreams. One study claimed that melatonin levels do not decrease with age, except maybe at night, although due to diseases or drugs elderly persons can have low levels of melatonin (Zhao et al., 2002). Melatonin may also aggravate asthma.

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, though this is outside the scope of 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 (reviewed in Dominguez et al., 2009).


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 (Ames et al., 1993). 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 although they can at times slightly increase longevity (Harman, 1968; Comfort et al., 1971; Heidrick et al., 1984; Holloszy, 1998; Saito et al., 1998). Vitamin C supplementation, for instance, does not affect lifespan in mice (Selman et al., 2006). Resveratrol, which is discussed in more detail elsewhere, and other red wine constituents can also act as antioxidants (Pervaiz, 2003) and might be protective agents of brain aging (Tredici et al., 1999; Bastianetto and Quirion, 2002; Mokni et al., 2007). So antioxidants might be healthy in the same way vitamin supplements, often including antioxidants, may be healthy; on the other hand, one large study found no evidence that multivitamin use influences mortality (Park et al., 2011). There is little evidence that these products have serious side-effects, though one study found that antioxidants can accelerate cancer development in mice (Sayin et al., 2014), and a shorter lifespan due to antioxidant supplementation has also been observed in voles (Selman et al., 2013). Overall, there is no 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).

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.

Telomere-Based Therapies

Telomerase is an enzyme that, at least in some cell lines, appears to overcome cellular senescence by 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 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 genes that hold promise for pharmaceutical intervention, and progress has been made in finding chemicals that can modulate specific aging-associated genes and 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).

The Not-So-Secret Guide to a Long, Healthy Life

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 alcohol intake and fruit and vegetable intake are associated with lower mortality (Khaw et al., 2008). Your doctor will be able to give you many more details on this topic and advise on the changes that may be more beneficial to your health in particular.


One question you may ask me is whether I take any of these so-called “anti-aging” products or supplements. The answer is no. I do not see evidence that any of these products, including caloric restriction, actually work; some might have health benefits but I am not convinced any can delay human aging. Besides, the aforementioned antioxidants and fish oil are good examples of the old idea that it is possible to purify the components of healthy foods to avoid having to eat them. So far, however, there is no evidence to suggest that these dietary supplements are an adequate replacement for a balanced diet, as pointed out by many others (Bjelakovic et al., 2007; Dominguez et al., 2009). For example, blood vitamin C levels have been associated with lower mortality (Khaw et al., 2008) yet vitamin C supplementation does not increase mouse lifespan (Selman et al., 2006). Most likely plasma vitamin C levels reflect fruit and vegetable intake, but it is not vitamin C alone that provides health benefits and cannot replace a diet rich in fruits and vegetables.

Overall, I do try to take some care of my health–like I think everyone should–by practicing regular exercise, not smoking, avoiding alcohol, and having a moderately balanced diet. My diet is not extremely healthy and so I have taken dietary supplements once in a while. Namely, I sometimes take vitamins (particularly in winter) and I used to take omega-3 fatty acids since I did not used to eat a lot of fish (but that has changed now). Ideally, my diet would be balanced enough to avoid having to take any supplements at all but I personally find it impossible. Anyway, that is as far as I go. I am not like that married couple who didn’t drink alcohol, didn’t smoke, didn’t eat meat, and even their children were adopted!

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