Aging is curable
Disease or not, aging is easily treatable
Mikhail V. Blagosklonny, Aging, 2018.
Translated by Evgenia Ryabtseva
For references and references, see the original article.
Is aging a disease? It does not matter, since aging is already amenable to therapy with a combination of several clinically available drugs, including rapamycin. The decision to classify aging as a disease depends on the subjective definitions of both diseases and aging itself. From the point of view of the goals of therapy, aging is a fatal disease (or rather a pre-illness), despite the fact that it is a normal continuation of the development of the body. It should and, very importantly, can be successfully treated in order to delay the development of classic age-related diseases, such as cancer, cardiovascular and metabolic diseases, as well as neurodegenerative diseases.
Endless debates about aging and diseases
For decades, one of the most discussed issues in gerontology has been the question of whether aging is a disease or the norm. To date, convincing evidence has been obtained in favor of the fact that aging should be considered a disease. There are all prerequisites for this, despite the fact that aging is the norm. Vladimir Dilman describes aging as a "normal disease."
Aging is a normal continuation of the development program, although it is not a program itself, but a meaningless unintended quasi-program. At the same time, aging is a fatal disease, since it invariably leads to death.
In fact, aging is the sum of all age-related diseases and this sum is the best biomarker of aging. Aging is inseparable from its diseases, since they are manifestations of aging. Of course, due to genetic and external factors, any age-related disease can develop at a young age. It is important that aging is a sufficient factor for the development of all age-related diseases, sooner or later, regardless of genetic and external factors: if Alzheimer's disease or type 2 diabetes has not been diagnosed throughout a person's life, this is due only to the fact that cancer or stroke interrupted his life before the disease could be diagnosed Alzheimer's or type 2 diabetes mellitus (and vice versa).
Aging is the sum of pre-illnesses and diseases
Aging increases the likelihood of death from age-related diseases, which are late manifestations of aging. The development of diseases is preceded by pre-illness. For example, diabetes mellitus is diagnosed in cases when the fasting blood glucose level is higher than 125 mg/dl, whereas values in the range of 100-125 mg/dl are considered indicators of prediabetes. It should be noted that diabetic complications, such as nephropathy and retinopathy, often develop even before the manifestation of type 2 diabetes itself. Despite the fact that prediabetes is not formally a disease, today it is treated in order to prevent the development of diabetes. Moreover, the development of prediabetes is triggered by processes called pre-prediabetes. They occur in the body when fasting blood glucose levels and tissue tolerance to glucose still do not exceed the norm, despite elevated levels of insulin in the blood (hyperinsulinemia), which indicates a small insulin resistance. Hyperinsulinemia in healthy adults against the background of normal glucose levels is a predictor of the development of type 2 diabetes mellitus over a 24-year follow-up period. Normal glucose levels (<100 mg/dl) in combination with hyperinsulinemia are pre-prediabetes. Hyperinsulinemia, in turn, can be triggered by a signaling mechanism mediated by the mammalian rapamycin target protein (mTOR). This leads to a state of pre-pre-prediabetes, in which both glucose and insulin levels are still normal. The condition, which we call pre-prediabetes, is associated with the development of diabetes mellitus, cardiovascular diseases in the future, as well as an increase in overall mortality. Preventive therapy with metformin begins to be used at very early stages of the disease in young people with obesity.
Another example is hypertension (a disease), which is described as an increase in blood pressure above 140/90 mmHg. Prehypertension (or borderline hypertension) is defined as blood pressure below 140/90 mmHg, but above 120/80 mmHg. Blood pressure increases more often with age and in people who do not those who have reached 140/90 mmHg (disease) or even 120/80 mmHg, (pre-illness) his indicators may be higher than at a younger age. Mortality is associated with high blood pressure, even if it is below 140/90 mmHg. Both prehypertension and prediabetes are age-related pre-diseases. Similarly, the asymptomatic stages of Alzheimer's disease are also a pre-illness.
With pre-illnesses, the severity of violations has not yet reached the subjective diagnostic criteria of the disease. Thus, aging consists of the progression of (pre)-pre-diseases (early aging) into diseases (late aging associated with functional extinction). Aging is not a risk factor for the development of these diseases, it consists of them: aging and diseases are inseparable from each other (Figure 1).
Figure 1. The relationship between aging and diseases. After the completion of the growth of the organism, its stimulating signaling pathways enhance cellular and systemic functions, thereby triggering the aging process. This is the stage of pre-pre-illness, a slow progression into the stage of pre-illness. Eventually, the changes reach the values of the clinical definition of the disease associated with organ damage, loss of function (functional extinction), rapid deterioration and death.
External signs of aging (such as gray hair, wrinkles, increased subcutaneous fatty retina and loss of muscle mass) they are manifestations of pre-diseases. For example, they may reflect hyperfunction of the adrenal cortex, sarcopenia, osteoporosis, skin pre-diseases, and so on. Age-related skin changes may portend the development of precancerous skin conditions.
What is "healthy" aging
What, then, is disease-free aging, the so-called "healthy" aging? "Healthy" aging is called subclinical aging, slow aging, or delayed aging, during which diseases remain at the stage of pre-diseases or even pre-diseases. In the end, diseases develop very quickly. "Healthy" aging is a state of pre-illness in which asymptomatic disorders have not reached the subjective values of determining diseases such as hypertension or diabetes mellitus. Instead of "healthy aging" we can use the terms "aging of pre-diseases" or "delayed aging". Moreover, delayed aging can be achieved by pharmacological methods. For example, rapamycin slows down aging, thus improving human health.
Currently, the term healthy life expectancy does not have clarity and accuracy, especially in relation to humans. Despite the fact that the duration of a healthy life depends on subjective criteria and subjective self-esteem, it is a useful abstraction. Theoretically, aging-slowing therapy increases both healthy life expectancy (preclinical period) and overall life expectancy, whereas therapy that increases life expectancy (for example, coronary artery bypass grafting, defibrillation) does not necessarily increase healthy life expectancy. However, the purpose of anti-aging therapeutic approaches, as well as preventive medicine, is precisely to increase the duration of a healthy life (by preventing the development of diseases), thereby increasing the overall life expectancy.
Preventive Medicine: a step towards anti-aging medicine
Aging is the sum of diseases and pre-diseases. Therapy is usually more effective at the stages of pre-illness associated with hyperfunction than at the aging of diseases associated with functional extinction. For example, rapamycin will not repair broken bones, but it can prevent the development of osteoporosis.
The goal of preventive medicine is to prevent the development of diseases by treating pre-diseases. Thus, preventive medicine is a form of anti-aging therapy. Both preventive medicine and anti-aging therapy should prevent the development of pre-diseases by treating "healthy" people. The drugs used by preventive medicine include statins, aspirin, angiotensin converting enzyme inhibitors (for example, lisinopril) and metformin, which can be used as anti-aging drugs. Conversely, the anti-aging drug rapamycin can become the cornerstone of preventive medicine. David Gems describes it as follows: "anti–aging therapy is any preventive approach to suppressing the development of late-life pathologies. Its implementation would facilitate the transition to a new level, as it would shift the focus to medical practice, especially the introduction of preventive approaches."
Treat treatable
The fact that aging is a mandatory part of the life of all organisms is not important. The important thing is that aging leads to death and, most importantly, is curable. Let's consider an analogy. Is the hair covering on the face (beard) in men a disease? Of course not. However, most men shave it off, effectively "fighting" this non-disease, simply because it is amenable to therapy. Is senile hyperopia a disease? It develops in almost all people by the age of 50 and is a continuation of the trends in the development of the eye. It is treated as a disease, as it is easy to cope with it with the help of glasses. Unlike senile hyperopia, menopause in women is usually not treated, since it is not easy to cure it. Thus, the choice between treatment and non-treatment is often based on the possibility of obtaining a result. It does not matter at all whether the target of therapy is a disease.
Aging is treatable
A simple example is the ability of a low-calorie diet to slow down the aging of various organisms, including primates. Similarly, short-term (periodic, interval") fasting and a ketogenic diet (strong restriction of carbohydrate intake) increase the life expectancy of mammals. A low-calorie diet (as well as limiting carbohydrate intake and short-term fasting) improves human health. However, following a low-calorie diet is very problematic for most people, and its life-extending effects are limited. Nutrients activate the nutrient-recognizing signaling pathway mediated by mTOR (the molecular target of rapamycin) and (above we will discuss the ability of mTOR to accelerate aging) inhibited by rapamycin.
Rapamycin and other rapalogs
Rapamycin (sirolimus), an allosteric inhibitor of the mTOR complex, is a natural rapalog, as well as the most powerful and best studied analogue of rapamycin. Analogues of rapamycin, such as everolimus, temsirolimus (rapamycin precursor) and deforolimus (ridaforolimus) are now also widely used.
Rapamycin, everolimus and deforolimus slow down the geroconversion (transition to the phase of physiological aging). It has been suggested that rapamycin is able to slow down the aging of mammals. Since 2009, numerous studies have demonstrated that rapamycin increases the lifespan of mice even at the beginning of therapy at late stages of life, as well as with temporary or periodic use.
In these studies, it was shown that rapamycin has the greatest effectiveness in high doses. Its effects, as well as the effects of everolimus, persist after discontinuation of use, even with a single dose. An important fact is the possibility of achieving high peak concentrations with a single large dose of the drug.
In primates, the constant and / or variable use of rapamycin improves the state of metabolism. In a randomized controlled trial in middle-aged dogs, the side effects of rapamycin did not differ from the side effects reported in the placebo-treated control group.
Millions of patients with various diseases and conditions (for example, recipients of organ transplants) receive therapy with rapamycin (sirolimus). The typical dose of rapamycin for organ transplantation is 2 mg/day. A single dose of rapamycin at a dose of 15 mg did not cause undesirable side effects in healthy volunteers. Similarly, rapamycin at a dose of 8 mg per square meter of body surface area (about 16 mg) was also well tolerated by healthy male volunteers. Surprisingly, participants in the placebo group reported more "side effects" such as asthenia than participants taking rapamycin. In another study, a comparison with placebo did not reveal any real side effects induced by everolimus in the elderly. Moreover, everolimus does not inhibit, but improves immunity and suppresses the development of infections in healthy elderly people. In placebo-controlled studies, the side effects of rapamycin and everolimus were eliminated by dose reduction and discontinuation of therapy. Discontinuation of therapy due to toxicity was extremely rare. In volunteers (aged 70-95 years, average age 80 years), rapamycin therapy at a dose of 1 mg / day for 8 weeks did not raise questions from the point of view of safety. Matt Kaeberlein suggests that traditional doses of rapamycin may not be sufficient to maximize life expectancy.
Traditional medicines as anti-aging drugs
Metformin is used not only for the treatment of diabetes mellitus, but also for prediabetes to prevent its transformation into diabetes. Metformin reduces insulin resistance of tissues and body weight, preventing the development of diabetes, cancer and cardiovascular diseases. It is assumed that it can increase life expectancy and in fact metformin does reduce overall mortality. In general, doctors do not consider metformin as an anti-aging drug solely because life expectancy is expected to increase as a result of preventing the development of diseases. In mice, metformin increases both healthy life expectancy and overall life expectancy. It also increases the lifespan of C.elegans roundworms, which do not suffer from analogs of human diseases. Gerontologists consider metformin as an anti-aging drug that can be used in combination with rapamycin.
Angiotensin II inhibitors
Angeotensin converting enzyme inhibitors (captopril, lisinopril, enalapril and ramipril) and angiotensin II receptor blockers (valzatran, telmisartan, losartan) are widely used in the treatment of hypertension, which is a typical hyperfunctional disorder. Vasoconstriction, cardiomyocyte hypertrophy, beta- and alpha-adrenergic hyperstimulation lead to an increase in blood pressure (systemic hyperfunction), which, in turn, contributes to the development of stroke, myocardial infarction and heart failure. Angiotensin converting enzyme inhibitors and angiotensin II receptor blockers reduce vasoconstriction and prevent the development of cardiac hypertrophy. These drugs prolong life, as they help in the fight against deadly diseases.
The ability of angiotensin converting enzyme inhibitors to increase the life expectancy of rodents with normal blood pressure is noteworthy, which allows them to be considered anti-aging drugs.
Combinations of traditional drugs
Combinations of aspirin, beta-blockers and angiotensin converting enzyme inhibitors are prescribed to elderly people for the prevention of cardiovascular diseases. On the other hand, these drugs increase the life expectancy of rodents and fruit flies of fruit flies.
Typical combinations (polypreparations) include an antiplatelet agent (aspirin), a statin and two drugs that lower blood pressure, such as lisinopril, as well as a beta-blocker. Presumably, taking such combined drugs will reduce the 5-year probability of stroke by 50%. Aspirin, statins, angiotensin converting enzyme inhibitors, beta blockers and metformin also prevent the development of certain types of cancer and precancerous polyps.
Fighting aging through preventing diseases or preventing diseases through slowing down aging?
As mentioned above, aging is the sum of all age–related diseases, and this sum is the best biomarker of aging. Some believe that medications prevent the development of diseases by slowing down aging. On the other hand, it can be said that preventing the development of diseases slows down aging, which is the sum of all diseases and pre-diseases. If the drug prevents the development of diseases, it will increase life expectancy (obviously, by slowing down aging). If the drug slows down aging, it will prevent the development of diseases and increase the duration of a healthy life.
Experts believe that anti-aging interventions of a narrow spectrum of action (for example, cardiovascular polypreparation) will allow the introduction of a practice that will later expand to anti-aging interventions of a wider spectrum of action (for example, mimetics of a low-calorie diet).
Conclusion
Traditionally, it is believed that aging should be considered as a disease, which will contribute to the development of anti-aging therapeutic interventions. This attitude is doomed to failure, as it allows us to postpone the development of anti-aging interventions until regulatory authorities recognize aging as a disease, which will happen very soon. Aging should not be considered as a disease in need of treatment. Anti-aging drugs, such as rapamycin, delay the development of age-related diseases. If the drug does not delay the progression of at least one age-related disease, it most likely cannot be considered as an anti-aging drug, since by definition it will not be able to increase life expectancy (animals die from age-related diseases). If the drug is already used to treat a chronic disease, its effects on other diseases can be evaluated on the same group of patients. Aging can be treated as a pre-illness to prevent its transition into diseases. Combinations of drugs based on rapamycin include traditional drugs to increase life expectancy, used to treat and prevent age-related diseases. These combinations can additionally be combined with diets with a moderately reduced number of calories, physical activity and the prevention of stressful situations. In fact, this approach is already being used at the Alan Green Clinic in New York.
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