Aging (Albany NY). 2009 March; 1(3): 281–288

Cancer Center, Ordway Research Institute, Albany, NY 12208, USA

Humans die from age-related diseases, which are deadly manifestations of the aging process. In order to extend life span, an anti-aging drug must delay age-related diseases. All together age-related diseases are the best biomarker of aging. Once a drug is used for treatment of any one chronic disease, its effect against other diseases (atherosclerosis, cancer, prostate enlargement, osteoporosis, insulin resistance, Alzheimer’s and Parkinson’s diseases, age-related macular degeneration) may be evaluated in the same group of patients. If the group is large, then the anti-aging effect could be validated in a couple of years. Startlingly, retrospective analysis of clinical and preclinical data reveals four potential anti-aging modalities.

Problem And Solution

The discovery of anti-aging drugs is no longer a fantasy. Numerous genes for aging and longevity have been identified in diverse organisms, revealing potential targets for potential anti-aging drugs. But how could potential anti-aging drug be introduced to humans? There are two problems. First, the effect of anti-aging agents on human aging may require almost a lifetime to determine. Second, it is seemingly desirable to test anti-aging drugs in healthy individuals. However, all drugs have side effects. And, in healthy individuals, side effects would preclude clinical trials. How might these problems be solved? How could we validate anti-aging drugs in humans without life-long trials in healthy individuals?

The solution includes two steps. First, we must find an indication for a drug to treat at least one chronic disease. Then this drug could be tested in humans, not as an anti-aging drug, but as therapy for a particular disease. In fact this approach has been suggested for introduction of activators of sirtuins to the clinic. Second, we must find a biomarker of aging that absolutely predicts longevity. Then using this biomarker, the anti-aging effect could be evaluated in the same patients.

Disease-specific drugs versus anti-aging agents

Slowing aging would delay all age-related diseases. If a drug is effective against one particular disease only, such a drug is not anti-aging. And current drugs are not anti-aging. For example, insulin compensates diabetes. Yet, insulin does not treat cancer. And vice versa chemotherapy may treat cancer but does not treat diabetes. So neither chemotherapy nor insulin is an anti-aging modality. Furthermore, both insulin and chemotherapy may accelerate aging.

From metformin and calorie restriction to rapamycin

The underlying cause of age-related type II diabetes is insulin resistance. Insulin treatment does not ‘treat’ the cause, it just compensates for resistance. Unlike insulin, metformin, an oral anti-diabetic drug, restores insulin sensitivity in type diabetes type II. Remarkably, metformin decreases the incidence of breast cancer. Also, metformin is considered for cancer treatment and inhibits atherosclerosis in diabetic mice. Metformin is used to induce ovulation in patients with polycystic ovary syndrome (PCOS). Six months of 1700 mg/d metformin treatment improved fertility in anovulatory PCOS women. Given such effects on infertility, type II diabetes, cancer and atherosclerosis, it is plausible that metformin slows aging. In fact, it extends life span in rodents.

Calorie restriction (CR) extends life span from yeast and worms to rodents and perhaps humans. If we did not already know that CR slows aging, how might we figure that out based solely on clinical data? Unrestricted food consumption leads to obesity associated with diabetes, atherosclerosis, thrombosis, hypertension, cancer (especially breast, prostate and colon cancer), coronary heart disease, stroke, osteoporosis and Alzheimer’s disease. In other words, unrestricted eating in humans (ad libitum in rodents) accelerates most, if not all, diseases of aging. So we can conclude that CR delays all diseases of aging. This suggests that CR is an anti-aging modality. And it is known that CR extends life span in almost all organisms from yeast to mammals.

Numerous factors including insulin, glucose and amino acids activate the nutrient-sensing TOR (target of rapamycin) pathway. When the TOR pathway is activated, it acts via S6K to deplete the insulin-receptor-substrate (IRS1/2), causing insulin resistance. Metformin indirectly (by activating AMPK) inhibits TOR and thereby restores insulin sensitivity.

CR decreases levels of nutrients and insulin and thus de-activates TOR. It is possible that the anti-aging effects of CR and metformin are due to inhibition of the TOR pathway. Like CR, rapamycin decreases size of fat cells and animal weight. When rats (15 weeks old) were either treated 1 mg/kg rapamycin 3 times per week for 12 weeks, rapamycin decreased their weight. Mean adipocyte diameter was decreased from 36 μm to 25 μm. At the end of the study, mean body weight in the rapamycin-treated rats was 356 g instead of 507 g, in spite of comparable food intake. So rapamycin imitated CR. CR may also extend life span by activating sirtuins. Probably, sirtuins, AMPK and mTOR are linked in the common network.

Genetic inhibition of the TOR pathway slows down aging in diverse organisms, including yeast, worms, flies and mice. If genetic inhibition of the TOR pathway slows aging, then rapamycin, a drug that inhibits TOR, must slow aging too. Once used for any indication, even unrelated to age-related diseases (such as renal transplantation, for instance), an anti-aging drug should slow down age-related diseases such as cancer, osteoporosis and atherosclerosis. Rapamycin is already used in renal transplant patients.

If a drug is indicated to treat most age-related diseases, then this drug could be defined as an anti-aging drug. The probability that a non-anti-aging drug would have independent activities against all diseases is exceedingly low.

Rapamycin analogs are approved to treat certain cancers. Based on preclinical data, rapamycin has been considered in such pathologies as obesity, atherosclerosis, cardiac hypertrophy, aortic aneurysm, osteoporosis, organ fibrosis (liver, renal, cardiac fibrosis), neurodegeneration, Alzheimer’s disease, Parkinson’s disease, psoriasis, skin scars and keloids, multiple sclerosis, arthritis, and renal hypertrophy in diabetes.

In principle, life-extending effect of anti-aging drug might be limited by side effects. Although chronic administration of rapamycin is associated with some undesirable effects in transplant patients, they might be avoided by administrating rapamycin in pulses (for example, once a week). For example, chronic administration of rapamycin impairs wound healing. In theory, a pulse treatment might rejuvenate wound-healing cells. A single dose of rapamycin reverses insulin resistance, whereas chronic administration of rapamycin may precipitate diabetes in certain conditions. Clinical trials will be needed to determine benefits of pulse treatment with rapamycin. Alternatively, rapamycin can be combined with ‘complementary’ drugs. Thus, hyperlipidemia caused by rapamycin may deteriorate insulin-resistance. Yet, hyperlipidemia caused by rapamycin can be controlled by lipid-lowering drugs. A combination of rapamycin with resveratrol may be especially intriguing.

Conclusion

It was previously assumed that anti-aging drugs should be tested in healthy individuals. Ironically, the best biomarker of aging is the occurrence of age-related diseases. And this is how anti-aging drugs can be validated in the clinic (by showing that a putative anti-aging drug can prevent or delay the onset of all age-related diseases). Then such drugs could be approved for prevention of any particular age-related disease in healthy individuals. Thus, potential anti-aging drugs should be introduced to the clinical trials for therapy of a particular disease but be ultimately approved for prevention of all age-related diseases in healthy individuals. And this is synonymous to the approval of a drug as anti-aging.