Dr Elisabetta Burchi, MD, MBA
Translational Research Lead at Parasym.
Editor: Dr. Greta Dalle Luche, PhD, Head of R&D
In the last few decades, medicine has undergone a progressive transformation from being generally “sick-oriented” and focused on the treatment of diseases to becoming more holistically interested in risk factors and prevention of diseases. While this perspective shift has not yet been fully translated into clinical practice, research and contemporary culture may have already moved beyond. Nowadays many aspire to a “positive medicine” capable not only to recover, but also boost the wellbeing of individuals by fostering their self-efficacy towards a healthier and even happier life. At this new frontier of healthcare, there is the interdisciplinary field of geroscience that studies the conditions associated with growing older with the goal to extend the healthy and active years of life.
Is ageing an irreversible phenomenon? The mission of geroscience
Senescence, namely the increase in the chances that an organism will lose functionality as it ages, has always been deemed as a biologically irreversible phenomenon. Consequently, ageing has never been treated as a disease, despite being found to be a major risk factor for a great number of illnesses ( including cardiovascular diseases and cancers) all directly related to a decrease in quality of life and an increase in mortality risk.
More recent experimental data has complemented such epidemiological evidence and shown a causal connection between ageing and the increased occurrence of chronic age-related diseases (ARDs). New evidence is pointing at a common set of basic biological mechanisms that would underpin both ageing and ARDs. A main consequence of this thread of research is that a primary target of medicine should become the ageing process over the single ARcouldshould be a legitimate goal of medicine.
Chronological vs biological age
As a modern iteration of the ancient tradition of the elixir of life, geroscience shows that it is scientifically possible to change the trajectory of degeneration encoded in our biology. This new approach that sees ageing as a reversible phenomenon and modifiable risk factor derives from a particular line of reasoning known as “disposable soma theory”. In brief, the theory describes the ageing phenotype as the result of the progressive accumulation of molecular damage that outsets the cellular maintenance systems. These maintenance mechanisms protecting the cellular status quo at some energetic costs have been found to be modulated by various factors, from nutrition to stress management. It is the possibility to modify these ageing factors and their dynamic interplay either at a molecular, behavioural, or environmental level, that creates the opportunity to delay, control, or avoid age-related diseases and ultimately the ageing phenotype.
This new understanding of ageing has prompted the identification of biomarkers that could be better used to describe an individual’s functional capacity, well-being and risk of developing ARDs and ultimately substitute the static concept of chronological age with the dynamic concept of biological age.
A potential biomarker that has gained significant interest in recent years is DNA methylation. Estimates of biological age based on combinations of methylation values at specific sites in the genome (i.e. epigenetic clocks) have shown to be much more capable of making predictions about ageing outcomes, including all-cause mortality, healthspan, physical and cognitive functioning, than chronological age and, notably, to differentiate morbidity and mortality risk among same-age individuals.
How to revert biological age: potential targets and potential interventions
The presence of multiple diseases and medical conditions in the same person, the so-called “multimorbidity”, can be seen as a multisystem manifestation of an advanced stage of ageing. In this framework, targeting conserved ageing pathways would potentially disrupt the treatment and trajectory of many chronic age-related clinical problems. To paraphrase what was said earlier, if chronological age is by definition an unidirectional vector, biological age can potentially be modified along with most of the age-related health outcomes.
This expectation is supported by several studies conducted in model systems that have elucidated the role and plasticity of many ageing cellular pathways. For instance, the Target of Rapamycin (TOR) and insulin signalling pathways are remarkably conserved across wide evolutionary distances and the fact that targeting these pathways increases both lifespan and healthspan in model organisms has brought to the fore the idea of interventions in humans.
Other biomarkers of ageing have emerged from exquisite longevity studies in humans. There is large evidence that increased activation of pro-inflammatory and interferon pathways increases biological (i.e. epigenetic) age relative to chronological age. On this basis, “inflammaging” – the increase in inflammation biomarkers during ageing – is now considered to be a robust hallmark for accelerated ageing (Inflammation – A Double-Edged Sword).
Other studies have highlighted that ageing is associated with hyperadrenergic states with imbalances in autonomic nervous system activity being the whistle-blower of vascular risk and the actor of vascular health. Measures of autonomic imbalance, such as a declining heart rate variability (HRV)(Autonomic tone and heart rate variability), could be biomarkers of advanced biological age. Poor HRV has been recognised as a relevant factor in the development of many different pathologies. For example, the consequences of decreased parasympathetic activity have been explored in large stroke cohort studies and it has been hypothesised that longevity could be promoted by decreasing sympathetic overdrive. Indeed, studies done in centenarians suggest that high HRV may play a role in exceptional longevity. Nurosym’s neuromodulation of the autonomic system has been proven to increase HRV in healthy individuals as well as in complex patient populations, including those with serious cardiovascular diseases. Autonomic nervous system neuromodulation appears the most effective in individuals who present with a lower vagal tone, suggesting that it might have an overall rebalancing effect on the autonomic system rather than an enhancement of the parasympathetic effect. While it is not demonstrated that increasing HRV leads to increased longevity, the benefits of autonomic rebalancing in chronic conditions driven by autonomic dysregulation (such as heart failure) is being increasingly recognised.
The protective effects of the cholinergic antiinflammatory pathway activated during parasympathetic activity, have been shown in animal models of myocardial infarction/ischemia-reperfusion. Evidence in humans supports a protective role of the vagus nerve in cancer and specifically in the metastatic stage, probably mediated by both reduction in oxidative stress and in excessive sympathetic activity.
Further recent research has demonstrated that human biological age is sensitive to specific interventions. Although the key molecular players that mediate the protective effects still need to be fully clarified, there is strong evidence that caloric restriction and lifestyle changes involving exercise, are capable of slowing down or even reversing the biological clock. Ongoing clinical trials are testing Vitamin D, metformin, rapamycin, senolytics, NAD precursor and Sirtuin-activating compounds for their potential to increase health and lifespan.
Vagal neuromodulation has shown exciting potential as a therapeutic intervention in cognitive decline by regulating cerebral perfusion and improving parasympathetic modulation of the cardiovascular system, as well as in cancer progression by reducing oxidative stress, systemic inflammation, and sympathetic activity and increasing cellular immunity.
Bryan Johnson’s project Blueprint: combining age-controlling factors
In the complicated path towards full understanding of the interplay between the factors that affect the ageing process, someone might be tempted to try to accelerate the translation of the latest findings into potential clinical and lifestyle interventions, simultaneously following and disregarding the paradigm of research.
Bryan Johnson is a successful entrepreneur, founder of Braintree Venmo and Kernel, that in 2020 launched “Project Blueprint”, an endeavour with the aim to reveal the status quo of today’s anti-aging science. The radicality of the project is embedded in the methodology: Bryan has put together a world-class team of doctors and researchers to track the biological vs chronological age of his own 78 organs in response to nutritional, behavioural, pharmacological, neuromodulatory interventions designed by the team and informed by the latest scientific evidence. The goal is to come up with a daily diet and exercise routine optimised to reverse the biological age of Bryan’s organs and potentially extrapolate a list of interventions that could be adopted by other followers. Consistent with this goal, Bryan and his team are constantly publishing the entire course of treatments and test results in full transparency and parallelly producing a simplified “starter guide” with diet suggestions, supplements and measurements to track progress.
Bryan’s current protocol is rigorous: it includes strict guidelines for diet (1,977 vegan calories a day dispensed through specific meals and recipes, 26 supplements including metformin and micro doses of lithium), exercise (a hour-long workout consisting of 25 different exercises), sleep (at the same time every night, after two hours wearing glasses that block blue light). In the interest of fine-tuning this program, Mr Johnson constantly monitors his vital signs and endures dozens of medical procedures. This daily regimen is complemented by other weekly procedures, featuring dozens of medical procedures, and specific training, such as the “5 hour rejuvenation athlete training” that features as first step vagal neuromodulation using Nurosym for the relative HRV protocol.
Bryan’s results from 2 years of Blueprint are impressive. Last year he reduced his epigenetic age by 5.1 yrs in 7 months and slowed his rate of ageing by 28%, that means for every 365 days, he ages 277 days.
Notably, despite the strict routine imposed by the lifelong experiment, Bryan says that he has never been happier in his life – not only because of the results achieved in terms of decelerated ageing, but mainly because of a new way of living life. The start and main goal of the blueprint project goes beyond aesthetic and physical rejuvenation. Bryan’s possibly main goal is to empower his own body to speak for itself in terms of its biological needs to break free of self-destructive behaviours and achieve optimal mental clarity for deliberate decisions regarding other aspects of life. The paradox is strong but meaningful: automating important functions to feel more human.
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