11 October 2011

How to check "pills for old age": in search of a panacea

Checking the effectiveness of aging-slowing drugs by treating age-related diseases
(ending, the previous part of the article – Drugs that slow down aging).

Numerous indications for taking one drugIf the drug is indicated for the treatment of most age-related diseases, it can be considered a drug that slows down aging.

The possibility that a drug that cannot slow down aging will have independent mechanisms of action against all diseases is negligible.

Rapamycin analogues are approved as agents for the treatment of certain types of cancer [45]. Based on preclinical data, rapamycin is recognized as effective as a remedy against such pathologies as obesity [58], atherosclerosis [53-55], cardiac hypertrophy [59-64], aortic aneurysm [65], osteoporosis [66-68], fibrosis of internal organs (liver, kidneys, heart) [64, 69, 70-75], neurodegeneration [76, 77], Alzheimer's disease [78, 79], Parkinson's disease [80-82], psoriasis [80], scars and keloid scars [83], multiple sclerosis [84], arthritis [85, 86] and kidney hypertrophy in diabetes [87].

Can rapamycin increase a person's life expectancy?In principle, the life-prolonging effect of an aging-slowing drug may be limited by side effects.

Despite the fact that the constant intake of rapamycin is associated with the occurrence of a number of adverse events in kidney transplant patients (see the list of references to the article [88]), they can be avoided by pulse application of rapamycin (for example, once a week). Although the constant use of rapamycin may disrupt the wound healing process, theoretically pulse therapy can restore the cells necessary for healing [88]. A single dose of rapamycin eliminates insulin resistance, whereas its constant use in certain conditions can contribute to the development of diabetes. To determine the effects of rapamycin pulse therapy, it is necessary to conduct clinical studies. Alternatively, rapamycin can be used in combination with "auxiliary" drugs. Thus, hyperlipidemia caused by rapamycin may exacerbate insulin resistance. However, it can be controlled with cholesterol-lowering drugs. The combination of rapamycin and resveratrol looks especially promising.

ResveratrolResveratrol, an activator of the mammalian SIRT1 protein, increases the life expectancy of representatives of various animal species [89, 90].

The ability of resveratrol to prevent the development of cancer, atherosclerosis, neurodegeneration and insulin resistance (type 2 diabetes) has been demonstrated [10, 91-100]. Resveratrol also indirectly inhibits the signaling mechanism mediated by PI-3K (phosphatidylinositol-3-kinase) – mTOR –S6K [101-105]. Mammalian SIRT1 and TOR may be components of the same sirtuin/TOR system. It has been suggested that there is a relationship between TOR and sirtuins [28]. It is likely that TOR (an aging-promoting mechanism) and sirtuins (an aging-slowing mechanism) are antagonists with respect to each other [106]. However, the inhibition of the TOR-mediated signaling mechanism occurs at concentrations of resveratrol close to toxic [107].

The ability of resveratrol to increase life expectancy may be limited by the manifestation of undesirable side effects caused by its toxicity in high doses. Therefore, clinical studies are conducted using more selective activators of the SIRT1 protein [3]. It is also important to note that similar drugs will be developed for the treatment of age-related diseases, such as type 2 diabetes [3]. This strategy of introducing the drug into clinical practice is the only acceptable one. However, there is another additional aspect: it is also the only practical approach to assessing the effect of slowing down aging. When used to treat diabetes, sirtuin activators can delay the development of heart disease, cancer, neurodegeneration and other age-related diseases in the same patients. And delaying the development of all diseases should increase life expectancy, thus confirming the ability of the drug to slow down the aging process.

ConclusionPreviously, it was believed that aging-slowing drugs should be tested on healthy individuals.

Paradoxically, the optimal biomarker of aging is the occurrence of age-related diseases. It is with the help of this marker that the clinical effects of aging-slowing drugs can be assessed (by demonstrating the ability of a potential aging-slowing drug to prevent or delay the appearance of age-related diseases). After that, such drugs can be approved as means for the prevention of certain age-related diseases in healthy individuals. Thus, drugs that potentially slow down aging should be used in clinical trials as a means to treat a specific disease, but the ultimate goal is to approve their use for the prevention of age-related diseases in healthy people. And this is equivalent to the approval of the drug as an anti-aging agent.

The list of references to the article “Validation of anti-aging drugs by treating age-related diseases" is given in a separate file.

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