Geroprotectors: a search strategy

The most effective personal anti-aging program

Numerous links to publications can be found in the original article:
Josh Mitteldorf, The Most Effective Personal Anti-aging Program

What are the most effective actions you can take to slow down the aging process and increase life expectancy? To answer this question, I have organized clinical trials. But before starting the study, we have to choose what we will evaluate, build a hypothesis. My idea is to combine the opinions of experienced professionals with the "people's choice" of which dietary supplements, habits and practices are worth evaluating.

The details of the research were described last spring in two materials. The results will be evaluated based on blood tests before, during and after the two-year studies. For the assessment, we do not use mortality or any health indicators, but methylation patterns, which, we hope, will make it cheaper and faster to get results. We will have enough resources to check dozens of different parameters at the same time, which in itself is a revolutionary step.

Many interventions are supposed to increase life expectancy by a year or more. Of course, I want to know which of them are the most profitable and promising. But more importantly, we want to know how they interact with each other. If any of these parameters in itself suggested serious benefits - say, an additional 20 years of life – its consequences would be so obvious that we would probably already know about it. Similarly, if these parameters add up to 20 years of life, we would all know some people who are clearly younger than their chronological age. In this regard, closer attention should be paid to various combinations of supplements, drugs, habits and practices. The combination of metformin with berberine and gynostemma can provide a slightly increased life expectancy compared to the use of any of them separately. A variety of different combined anti-inflammatory strategies may be slightly more effective compared to taking aspirin daily.

But we hope there are exceptions. If two different parameters act on completely different metabolic pathways, then we can only hope that their effects should overlap. For example, it is possible that life extension is based on mitochondrial health, synergistic with interventions based on rebooting the immune system. Then we could hope that these two parameters together give a greater increase in life expectancy than the sum of what they give separately.

Research design

We will not tell people who decide to take part in this study what to eat, what pills to take, or how much to exercise. We will ask people to fill out a questionnaire about what they do, what they eat, and what supplements they take. We will select the parameters so that they represent a wide range of possible strategies and various combinations between them – wide, but not too wide.

We will have enough statistical power to estimate the interactions between each pair of parameters out of 12, which we take as independent variables. These 12 should be selected in advance so that the study has a clear focus. If there are more than 12 of them, the number of interactions will also increase significantly. I decided to start with 15 and highlight the list after the participants register for the study.

Here are the criteria I propose:

▪ For each parameter separately, there should be either data on human mortality or data on longevity.
▪        These parameters should be easily accessible to everyone.
▪        It should be known about these parameters that they are already in common use (and we will have no problems identifying various groups of subjects who use them).

I find it difficult to limit this list to 15. It may make sense to include several parameters that each participant will be required to complete in order to be included in the study. Here we could include the following:

▪        Smoking cessation
▪ Limited use of alcohol (or refusal of it)
▪        Taking vitamin D at least 5000 IU daily
▪ Multimineral supplement with magnesium, zinc, chromium and selenium
▪ Exercises equivalent to at least 5 hours of walking per week or yoga.

Body weight is an important factor of longevity, which is difficult to take into account. Studies show that maximum life expectancy is associated with a body mass index (BMI) from 21 to 25, but in my interpretation, a lower BMI is always beneficial for any individual.

The reason for the apparent paradox is that people have a genetic predisposition to overweight or underweight. Those who are genetically prone to underweight tend to overeat because they can do it without being censured by society. Those who are genetically prone to being overweight are forced to limit themselves in food all the time (women are more than men), as well as limit calories in order to keep the BMI within 25. These diets allow you to get the maximum benefit from calorie restriction, despite the fact that they do not make people slimmer.

A list of things that lengthen your life

1 Love. Among men who are married or in close relationships, the mortality rate is 7% lower than that of single men. Among women – by 4%. These figures correspond to less than one year of average life expectancy. Another study suggests that loneliness increases mortality by 50%, which corresponds to almost 5 years of life.

2       Confession. We spend up to 14 years of pure time at work, and I like to think that this is necessary more in order to feel our own need than to earn money.
3       Anti-inflammatory drugs: Aspirin, ibuprofen, curcumin or fish oil. Studies attribute about a year of extra life to taking aspirin daily.

4       High fiber content is the key to healthy intestinal flora. We know that this is important, but we do not yet know how to manage biota to achieve maximum life expectancy.
5       Vegetable diet. Scientists come to the conclusion that vegetarians live on average 3 years longer, but the methods and results vary significantly from study to study.
6       Meditation. The influence of such a parameter as the practice of meditation is difficult to assess, and the information available on this subject is unreliable, although encouraging. The only thorough study links meditation not with mortality, but with telomerase activity. I admit that I included meditations in the list based on my own intuition and experience.
7       Periodic fasting increases life expectancy in mice and reduces mortality in nursing homes.
8       Interval training is considered the most effective for strengthening the cardiovascular system; there are few data on their positive impact on all causes of mortality.
9 I also included blood donation in the list on a whim, but there is evidence to support this, which I described a few years ago.
10 N-acetylcysteine: only one study showed a 30% increase in the lifespan of mice.
11 A low level of dehydroepiandrosterone in the blood is unambiguously associated with a greater age and a higher mortality rate among peers, but the direction of the causal relationship has not yet been established.
12 Metformin has been prescribed for diabetes for many decades, this drug also reduces the mortality rate from cancer and heart disease.
13 Rapamycin. The most convincing data among all supplements were obtained in mice. Pioneers begin to experiment on their own.
14     Quercetin + Dasatinib (or other senolytics). Senolytics in the short term are the most promising means in anti-aging medicine; but the safety of the combination of quercetin + dasatinib for humans has not yet been fully investigated: its use leads to the death of too many ordinary cells.
15 Epithalamin. Promising data have been obtained in Russia, both in rodents and in humans, but no one has tried to reproduce these data in the West.
16 Ashwagandha (many benefits, but no data on the impact on mortality and life expectancy).
17 Selegiline (deprenyl). In the classic studies of the 1980s, the life expectancy of rats increased. The data obtained on humans are contradictory.

Perhaps we should start by assuming which combinations might be redundant. So we could put together different strategies and combine more strategies into a list. It might look like this:

1       Anti-inflammatory drugs (aspirin, ibuprofen, statins, omega-3, curcumin, boswellia 2 Control of blood sugar concentration (metformin, berberine, gynostemma, chromium)

3       Social factors (family, employment, well-being, social status, marriage, sex, communication with nature, recognition)
4       Mitochondrial supplements (N-acetylcysteine, coenzyme Q10, vitamin B14, HP, melatonin, glutathione, carnosine, alanine)
5 Immune support (reishi mushrooms, cistanche, andrographis, hydrastis, echinacea)
6       Adaptogens (rhodiola, ashwagandha, bacopa, silymarin, pycnogenol)
7       Telomerase activators (silymarin, astragalus, ashwagandha, goryanka)
8       Senolytics (quercetin, dasatinib, fasting)
9 Diet (all food from high-protein to high-fiber, to veganism, to paleo in one item?)
10 Restrictions and breaks in the diet (long and short-term fasting, calorie restriction)
11 Exercises (aerobic, strength, interval, walking, sports competitions, yoga)
12 Mental concentration (meditation, prayer, yoga, tai chi, spiritual practice, caffeine)
13 Neuroprotectors (ashwagandha, rhodiola rosea extract, ginkgo extract, melatonin, bacopa, selegiline, gotu kola, coffee, tea, blueberries, chocolate)
14     Multivitamin complexes (including mega-D, Mega-C, B12, carotenoids and tocopherols)
15     Sex and steroid hormones (dehydroepiandrosterone, prostaglandins, progesterone, testosterone, S-adenosylmethionine)
16 Angiotensin converting enzyme inhibitors (Lotensin, Captopril, Enelapril)

Or, taking the best of both options, we could structure the study in such a way that its results could be analyzed both in terms of individual strategies and their complexes.

The best way to learn something is to start from the end. If two years ago, when I was at the very beginning of this path, I would have looked at the results of 5,000 people in the context of increasing life expectancy, then the first thing I would have noticed was the sharply distinguished values. Are there people among the subjects who stand out from the normal distribution curve, aging much slower? If so, what do they have in common? The advantage of this approach is that it provides maximum flexibility in highlighting exactly the information we are interested in. The disadvantage is that it is easy to be deceived and see patterns in a small set of random errors. When there is no initial hypothesis, there is no objective way to calculate the probability that what we see is the result of chance.

Our null hypothesis is that there is no systematic spread of values, but only a "smooth tail" to the probability curve. If there are several individual individuals out of these 5,000 who age significantly slower than the rest, and we cannot find a relationship between them, then we will interpret these data as anomalies or errors. If this is our result, it will bring disappointment, sobering up, but it will also give us some freedom.

But there is a chance that we will find something more interesting. We may find that there are dozens of stand-out values, that their strategies for increasing life expectancy intersect in some well-known and unambiguous ways. Then, for the first time, we will have a solid foundation for highlighting our personal life-prolonging habits, and clear hypotheses for further experiments.

Translation: Anastasia Poznyak, portal "Eternal Youth" http://vechnayamolodost.ru /.