Recent studies on longevity, both the longevity of centenarian populations and studies on cellular longevity, demonstrate very clearly that the most important benefits come from synergistic effects. This complicates scientific studies, but at the same time highlights the possibility that there are other unsuspected synergistic effects that could be of great importance to human health. Recent findings from our work on cellular longevity with Concordia University point in this direction.
The scientific approach
The usual scientific approach consists of making a hypothesis aimed at a single factor and isolating it as much as possible in order to propose an approach to verify this hypothesis (for example: does omega-3 have a significant impact on cardiovascular health?). However, it is evident that human health is influenced by a multitude of factors, simultaneously rather than independently. Thus, some benefits may be difficult to study due to the presence of confounding factors that positively or negatively influence the results of the study. Statistical analyzes usually allow them to be taken into account when they are identified. In some cases, these confounding factors could even be the source of the benefit by allowing a synergistic effect which makes the studied effect significant. This, for example, explains the effectiveness of a large number of plant extracts among natural products. When the main active ingredient is isolated, often the effectiveness is no longer significant because it depends on several mechanisms of action. This is the case, among others, for valerian (Shinjyo et al., 2020) and devil’s claw (Georgiev et al., 2013).
The synergy of lifestyle
The study of centenarian populations shows us that eating well is not enough to live up to or more than one hundred years old, and that several factors are important for healthy longevity. For example, centenarians with the typical personality of people who age well (optimistic, extroverted, pleasant, having a great capacity to express their emotions) retain better cognitive abilities than centenarians with a negative personality. Several studies have also shown that the quality of relationships and social life, can be used to predict both the state of health as we age, as well as the cognitive abilities that people will retain. Could it be possible, for example, that the positive personality typical of centenarians, facilitates the quality of relationships? I think this is obvious, as is the ability to express our emotions.
Coming back to diet, the Mediterranean diet is probably the most studied. It reduces the incidence of a large number of cancers, but also mortality from all causes. However, several recent studies point out that it’s not just what you eat, but also when you eat it that is important. Intermittent fasting and calorie restriction are said to have very big impacts on the benefits of the diet. What if we have the right personality and the right diet?
I have mentioned several times in my books that what makes the successful aging of centenarians (healthy longevity) is not one, two, or even three factors, but the synergy produced by all of their habits of life combined.
Even within the Mediterranean diet, certain components are said to have synergistic effects on the functioning of the human body. I could tell you about recent scientific publications, but also about our discoveries with Concordia University (https://esimard.com/recherches/).
In particular, hydroxytyrosol, the main olive polyphenol, which was categorized as a gerosuppressive agent (Menendez et al., 2013), protecting against aging via AMPK and autophagy (de Pablos et al., 2019), would have synergistic effects with resveratrol. These synergistic effects could have an important role in the prevention or treatment of neuronal or muscular degeneration (Petrella et al, 2021).
Another example with hydroxytyrosol that demonstrates the complexity of studying the impact of multiple factors is its effect on omega-3 metabolism (Valenzuela et al., 2017). It would promote a greater presence of omega-3 in the tissues through a targeted action on the reduction of oxidation and desaturases (an enzyme that increases the number of unsaturated bonds of fatty acids).
Gerosuppressive agents from plant extracts
What if I told you that for cellular longevity, there are molecules that synergize the impact of all the other gerosuppressive agents? These universal “synegizers”, which are gerosuppressive agents, could have very important impacts on cellular longevity and healthy life expectancy.
It is important here to define what a gerosuppressive agent is. In the mid-2000s, the cellular processes of primary aging, which causes the body to age, were linked to calorie intake following multiple studies on calorie restriction. It was then possible to search for molecules that could slow down these processes. Some natural molecules have effects similar to calorie restriction. They are very few. The molecules capable of slowing down primary aging were then called “calorie restriction mimetics”.
We now call them gerosuppressive agents; from the Greek “gero” which means aging, and “suppressor” for the slowing down of the process. This term better represents the objective pursued. The term calorie restriction mimetic was not intended to reduce calorie intake, but to replicate the benefits by slowing down primary aging.
Our research with Concordia University, which has been supported by the Natural Science and Engineering Research Council of Canada (NSERC) since 2014, identified 21 new agents, all derived from plant extracts. This work initially aimed to validate two hypotheses: 1) the possibility of identifying new gerosuppressive agents and 2) that gerosuppressive agents which act on complementary metabolic pathways would have significant synergistic effects.
Know the complementary metabolic pathways
Our second hypothesis was based on the fact that there are 4 main metabolic pathways in primary aging associated with two major biological processes: the body’s urge to age and the mechanisms of maintenance and repair. Animals that live particularly long, such as bats (10 times longer than other organisms their size), optimize these two biological processes for healthier longevity. Thus, by acting on both types of mechanisms, it would be possible to reduce the body’s urge to age while increasing its maintenance and repair capacities.
This hypothesis was validated by our work and published in the scientific journal Oncotarget (Dakik et al., 2019). During this work, we also identified 3 gerosuppressive agents which are universal synergizers. That is, all of the gerosuppressive agents that we tested in combination with these molecules showed considerable synergistic effects up to a more than 1000% increase in cellular longevity. We have filed for patents to protect this important discovery. Among these universal synergizers are resveratrol (which is found in small amounts in different foods such as grapes, dark chocolate or red wine) and spermidine (pineapple, caper, hazelnuts, almonds, pistachios, chestnuts, etc.). The effects of resveratrol are possibly due to epigenetic modulation and sirtuins, which would stimulate maintenance and repair mechanisms to promote longevity (hypothesis). For spermidine, this could be related to autophagy mechanisms (hypothesis).
The other identified gerosuppressive agents all come from plant extracts known for other health benefits: (PE for “plant extract”) PE4 (Cimicifuga racemosa), PE5 (Valeriana officinalis L.), PE6 (Passiflora incarnata L.), PE8 (Ginkgo biloba), PE 12 (Apium graveolens L.), PE21 (Salix alba), PE26 (Serenoa repens), PE39 (Hypericum perforatum), PE42 (Ilex paraguariensis), PE47 (Ocimum tenuiflorum), PE59 (Solidago virgaurea) , PE64 (Citrus sinensis), PE68 (Humulus lupulus), PE69 (Vitis vinifera), PE72 (Andrographis paniculata), PE75 (Hydrastis canadensis), PE77 (Trigonella foenumgraecum), PE78 (Berberis vulgaris), PE79 (Crataegus monogyna), PE81 (Taraxacum erythrospermum), and PE83 (Ilex paraguariensis).
The synergy of health approaches – integrative health
Some of these gerosuppressive agents, such as olive polyphenols, resveratrol and those found from celery seed, can be found in significant amounts in our diet. Besides their gerosuppressive effects, they could have synergistic effects amongst one another.
Likewise, it seems obvious to me that it will be possible to optimize human longevity by synergizing healthy lifestyles (including healthy eating) and gerosuppressive agents: lifestyle + healthy eating + supplements = optimization. Naturopaths are ideal resources to support you on this path.
When necessary, it will of course also be relevant to consider the synergy of therapeutic approaches in order to optimize the services offered. The synergy of healthy approaches should give better results than always considering only one approach at a time. For example, a recent study (Xi et al., 2021) demonstrated better results for the treatment of chronic obstructive pulmonary disease (COPD) by combining the approaches of modern medicine with Traditional Chinese Medicine. This is a confirmation of the importance of integrative health.
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- Robert Waldinger : Qu’est-ce qui nous garde heureux et en bonne santé tout au long de la vie ? – TED Talks
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