24 August 2015

Slowing down Aging: Are we ready? (1)

Translated by Evgenia Ryabtseva.

The time has come when it is necessary not only to consider certain therapeutic techniques as means for the treatment of age-related diseases, but also to begin conducting appropriate clinical studies.

ResumeSeminar entitled "Interventions aimed at slowing human aging: are we ready?"

It took place on October 8-13, 2013 in Eritz, France. Its purpose was to meet leading experts in the biology and genetics of aging to reach consensus on the search and development of safe interventions aimed at slowing down aging and increasing the duration of a healthy human life. As a result, a consensus was reached according to which scientists have convincing evidence that interventions in the aging process will delay and prevent the development of many chronic diseases of adult and senile age. The most important mechanisms were also identified and behavioral, dietary and pharmacological approaches were formulated. Despite the fact that a large number of target genes and drugs were discussed and that no complete consensus was reached on all interventions, the participants identified a number of the most promising strategies whose impact on life expectancy could be tested in clinical studies. 

These include: (1) dietary interventions that mimic chronic calorie restriction (periodic fasting, restriction of protein intake, etc.), (2) drugs that inhibit the signaling mechanism mediated by growth hormone and insulin-like growth factor-1 (IGF-I), (3) drugs that inhibit the signaling mechanism mediated by mammalian rapamycin target protein (mTOR) and S5 kinase (S6K) and (4) drugs activating AMP-dependent kinase (AMPK) or specific proteins of the sirtuin family. 

The choice made was partly based on convincing evidence of longevity-enhancing effects or the ability of these interventions to prevent or delay the development of a variety of age-related diseases and improve the healthy life expectancy of simple model organisms and rodents, as well as their potential safety and effectiveness when used to increase the duration of a healthy human life. The authors of this article were invited to the seminar as speakers and panelists. The following summary of the seminar describes the main issues considered and the conclusions formulated as a result of the discussion.

IntroductionHuman aging and age-related diseases acquire the status of one of the most significant problems and financial burdens faced by developed and developing countries (Christensen et al., 2009).

Despite the fact that there has been a significant increase in average life expectancy over the past 100 years, this has not led to an equivalent increase in healthy life expectancy (Hung et al., 2011). Studies on the possibilities of increasing longevity have traditionally been viewed with skepticism and concern that the result may be an increase in the population of older people and the incidence of age-related diseases. However, studies on various model organisms have shown that a marked increase in life expectancy in most cases is accompanied by a decrease or delay in morbidity (Fontana et al., 2010). 

The results of experiments on rodents consistently indicate that both chronic calorie restriction and mutations affecting the functioning of growth signaling mechanisms can increase life expectancy by 30-50%. Such interventions can also reduce the frequency of age-related loss of function and a variety of diseases, including tumors, cardiovascular diseases and neurodegeneration (Fontana et al., 2010). A low-calorie diet protects rhesus monkeys from diabetes, cancer, cardiovascular diseases, sarcopenia and neurodegeneration of certain brain regions, and also increases their life expectancy (Mattison et al., 2012; Colman et al., 2014). In humans, prolonged adherence to a low-calorie diet causes a number of metabolic and molecular rearrangements that protect the body from age-related pathologies, including type 2 diabetes, hypertension, cardiovascular diseases, cancer and dementia (Cava & Fontana, 2013). Moreover, chronic restriction of caloric intake weakens the severity of expected age-related changes in the elasticity and autonomous functioning of the myocardium, as well as gene expression in muscle tissue (Mattison et al., 2012; Cava & Fontana, 2013; Colman et al., 2014). 

However, the duration and severity of the low-calorie diet regime required to get the maximum benefit is unacceptable for most people and is likely associated with undesirable side effects. Therefore, the consensus reached in this case implies the use of less radical dietary interventions and drugs that affect nutrient-sensitive signaling mechanisms and have effects similar to those of a low-calorie diet, while being practical, realistic and safe.

The expert Group reached a full consensus on the following issues: (1) aging can be slowed down with a variety of interventions; (2) slowing down aging usually delays or prevents the development of a number of chronic age-related diseases; (3) dietary, nutraceutical and pharmacological interventions modulating the relevant intracellular signaling mechanisms and potentially applicable to humans have already been identified. As research progresses, additional potential targets will appear and (4) at this stage, it is necessary to proceed with caution to clinical trials of these interventions. Based on the results of the voting held on the last day of the seminar, a list of the most promising strategies according to the expert group was compiled. It is given below.

1. Pharmacological inhibition of the signaling mechanism mediated by growth hormone and insulin-like growth factor-1.2. Restriction of protein intake and diets reproducing the effects of fasting.
3. Pharmacological inhibition of the signaling mechanism mediated by mammalian rapamycin target protein and S6 kinase.
4. Pharmacological regulation of the activity of certain proteins of the sirtuin family, as well as the use of spermidine and other epigenetic modulators.
5. Pharmacological inhibition of inflammation.
6. Chronic use of metformin.

The main facts for each of the promising strategies are listed below. Other ideas discussed during the seminar are described in another publication (Gems, 2014).

Biomarkers for evaluating the effectiveness of interventionsBiomarkers of aging are necessary for the successful development and implementation of interventions aimed at increasing the duration of a healthy life.

Biomarkers are biological characteristics that can be objectively measured and evaluated as indicators of normal and pathological processes associated with age. In practice, such biomarkers should help in diagnosing human aging phenotypes, predicting the progression of these phenotypes, selecting possible interventions and evaluating the effects and results of such interventions. For example, in clinical trials, biomarkers can be used to divide patients into groups so that only patients who are most likely to respond to it receive a specific therapy. They can also act as intermediate results of evaluating the effectiveness and safety of interventions, testing of which often requires long time intervals. There are three categories of such biomarkers.

Biomarkers of critical aging-promoting mechanismsSuch biomarkers are necessary to determine the parameters that should be used as targets during interventions.

The disease can be described as a violation or anomaly of structure or function. Some experts have argued in favor of the fact that aging cannot be abnormal, since it affects every person. This approach, which makes it difficult to recognize aging as a disease, as well as the long period of time required to evaluate the effects of interventions, stand in the way of conducting clinical trials. That is why there is a need for biomarkers that predict the long-term effects of interventions.

Despite significant progress in our understanding of how the life span of experimental animals can be modulated, human aging is much less clear. The development of markers for processes recognized as critical for healthy human aging requires integrated animal and human studies. During their implementation, much attention should be paid to systems biology, which will help to understand the molecular foundations of critical aging-promoting processes that are the targets of interventions, as well as give a mechanistic explanation of potential interventions. It is also very important to collect data on epigenetic changes and rearrangements at the level of other "omics" that are potentially significant for critical molecular mechanisms that contribute to aging.

Related biomarkersFor each of the promising interventions, it is necessary to develop biomarkers that allow: (1) to identify individuals who can benefit from therapy and (2) to help in the study and evaluation of the molecular target(s) of the tested agent.

The high frequency of failures in clinical trials of new therapeutic approaches indicates the exceptional importance of finding biomarkers that allow predicting effectiveness.

Safety biomarkersThe development of 30% of new drugs is forced to stop at the level of clinical trials due to unforeseen toxicity or other undesirable side effects.

This is extremely important in the context of interventions in the aging process, since they cannot be easily tested in clinical studies and imply a long course of therapy. Therefore, special attention should be paid to the development of safety biomarkers. Also, in this case, some traditional biomarkers can be used, for example, when assessing toxicity to the liver and kidneys.

Concomitant biomarkers and safety biomarkers are not specific to aging and age-related diseases. The most difficult task is to develop a panel of biomarkers suitable for use in clinical trials, that is, biomarkers of the first of the listed categories. Below is a list of potential biomarkers or methods for assessing biological age and the risk of developing age-related diseases discussed during the seminar.

1. Standard assessment of the level of decrepitude (including walking speed in old age, hand compression strength, VO2max indicator – the body's ability to absorb and assimilate oxygen from the air).
2. Blood insulin level, insulin resistance, fasting blood glucose + glucose tolerance test, hemoglobin A1c (glycosylated hemoglobin) level, adiponectin level, assessment of fat deposits in the abdomen using two-photon X-ray absorptiometry.
3. Levels of low- and high-density lipoproteins in the blood, blood pressure, pulse wave propagation rate, thickness of the intima-media complex, diastolic function of the left ventricle.
4. Markers of inflammation (including C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha).
5. The level of cognitive functions (cognitive function testing, functional magnetic resonance imaging (fMRI).
6. The number of lymphocytes in the blood, the quantitative ratio of lymphoid and myeloid cells.
7. Insulin-like growth factor-1, thyroid hormone triiodothyronine (T3).
8. Epigenetic profile (including DNA methylation).
9. Renal clearance (age 60-90 years).

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