The Longevity Paradigm:Reimagining Ageing and Healthspan Potential

Human longevity, the quest to extend our lifespan beyond its natural boundaries, has intrigued humanity for centuries.

The Epic of Gilgamesh tells the tale of a legendary king of Uruk who embarks on a quest for immortality after the death of his friend Enkidu. Along the journey, he encounters trials, battles monsters, and ultimately fails in his pursuit to find the elusive plant at the bottom of the sea.

Finding the elixir of life has been the story throughout history, including that of Sir Galahad, an Arthurian knight who embarked on the quest for the Holy Grail in pursuit of immortality bestowed by the sacred chalice.

Gilgamesh and Sir Galahad can now be replaced by tech billionaires, venture capitalists, private equity and biotech startups.

In the modern age, our understanding of the science behind longevity has evolved significantly. Yet, fundamental questions persist, challenging us to explore deeper into the molecular mechanisms that govern ageing and longevity. In this article, we embark on a journey through the labyrinth of human longevity, pondering the mysteries that lie at its core.

At the heart of the pursuit of longevity lies the enigma of ageing itself. Ageing is a complex biological process, influenced by a myriad of factors ranging from genetic predispositions to environmental influences. But what exactly causes ageing, and can we intervene to slow down or even reverse its effects? These questions have long fascinated scientists and have given rise to a diverse array of theories and hypotheses.

One prominent theory that has garnered significant attention is the "telomere theory of aging." Telomeres are repetitive DNA sequences located at the ends of chromosomes, serving as protective caps that prevent genomic instability. However, with each cell division, telomeres progressively shorten, eventually reaching a critical threshold that triggers cellular senescence or death. This phenomenon is thought to contribute to the ageing process, leading some researchers to explore the potential of telomere maintenance as a strategy for extending lifespan. |

But telomeres are just one piece of the puzzle. The intricate dance of molecular pathways orchestrating cellular aging involves a multitude of players, each influencing longevity in its own unique way. From the intricate interplay of mitochondria and oxidative stress to the role of epigenetic modifications in gene expression regulation, the molecular landscape of ageing is rich with complexity and nuance.

One intriguing avenue of research is the study of sirtuins, a family of proteins implicated in various cellular processes, including DNA repair, metabolism, and stress response. Sirtuins have emerged as potential regulators of longevity, with studies suggesting that their activation may confer protective effects against age-related diseases. This has led to the exploration of sirtuin-activating compounds, such as resveratrol, as potential anti-aging interventions.

There are many start-ups in anti-ageing, such as Altos Labs and Clock.bio, Genflow Biosciences, Life Biosciences, New Limit, Rejuvenate Bio all with the aim to restore cell health and resilience through cellular rejuvenation programming or genetic modificationto reverse disease, injury, and disabilities. Genflow, already has a lead compound, called GF-1002, which is a suspension of an adeno-associated virus vector-based (AAV-based) gene therapy for intravenous infusion. The company uses AAV vectors to deliver copies of the Sirtuin-6 (SIRT6) gene variant, which is found in centenarians, into cells.

Lifespan and Healthspan

Lifespan and healthspan are two concepts often discussed in the context of human longevity and overall well-being:

Lifespan refers to the maximum duration of life that an organism, typically a human, can live. It is the total number of years an individual is expected to live, from birth until death. Lifespan is influenced by various factors, including genetics, lifestyle, environment, and access to healthcare. While the maximum potential lifespan for humans is believed to be around 120 years, the average lifespan varies significantly across different regions and populations.

The oldest person who ever lived was Jeanne Clement, who survived both world wars to the ripe age of 122. This is the extreme length of human existence. Although we are getting bigger and stronger, the biological processes that determine our existence have not changed.

The average age in the world is 73.4, varying from 85.5 Hong King to 53.7 in Chad. Japan has the most octogenarians, with more than one in 10 people over the age of 80 and

29.1% of the 125 million population is aged 65 or older. Japan has the world’s oldest population already has significant problems of population deflation with more people dying than being born.

Healthspan, on the other hand, refers to the period of life during which an individual remains healthy and free from chronic diseases or disabilities. It is not just about living longer but living better, with a high quality of life and functional independence. Healthspan is influenced by factors similar to lifespan, including genetics, lifestyle choices, environmental factors, and access to healthcare. Maximising healthspan involves promoting overall wellness, preventing disease, and maintaining physical and mental health as one ages.

The delta can be defined as the difference between lifespan and healthspan, and the idea of health must shorten this as much as possible. It may not be possible to lengthen lifespan, but it should be possible to improve healthspan with modern therapies and exponential technologies.

Longevity Clinics

There has been a recent proliferation of longevity and human performance clinics. Some are nothing more than modern snake oils offered to the most susceptible.

However, there are also clinics that are beginning to understand the biology, behaviour and take a multi modal approach which are promising.

Can we improve human performance and lifespan using external biometric performance data, internal biomarker testing, and health wearable data?

HUM2N , a UK company, aims to do just that, and I have had the pleasure of visiting the impressive clinic in London.

Here is a video of the CEO talking about the journey of patients incorporating hyperbaric 02 therapy, whole-body cryotherapy and herbal biohacking. Its CEO is, Dr Enayat , whom I often refer to as the Harry Potter of Longevity. I intend to put myself through their assessment and treatment and will report back of the outcomes and experience in updates over the next few months.

Longevity research

Another interesting venture is the Hevolution Foundation borne out by the covid pandemic in 2021. The Foundation, set up in Saudi Arabia, is a first-of-its-kind global non-profit organisation that provides grants and early-stage investments to incentivise independent research and entrepreneurship in the emerging field of healthspan science. I was fortunate to be at the Future Health Summit in Dubai in January and was impressed by the keynote of Dr Mehmood Khan. Saudi Arabia has of course grand ambitions with the development of NEOM a new gargantuan smart city/region, as part of the Kingdom's Vision 2030.

Epigenetics

Epigenetic reprogramming is indeed a promising approach in the field of anti-aging research. Epigenetics refers to changes in gene expression that occur without altering the underlying DNA sequence.

The primary goal of epigenetic reprogramming in anti-aging therapies is to reverse or modify these epigenetic markers associated with aging. This can be achieved by identifying specific sets of transcription factors or small molecules that can induce changes in gene expression patterns. By doing so, researchers aim to rejuvenate cells and tissues, potentially slowing down or even reversing the effects of aging and age-related diseases.

One approach to epigenetic reprogramming involves the use of induced pluripotent stem cells (iPSCs). iPSCs are adult cells that have been reprogrammed to behave like embryonic stem cells, which have the ability to differentiate into various cell types. By inducing pluripotency in adult cells, researchers can effectively reset their epigenetic state, essentially turning back the clock on cellular aging.

Another approach involves the direct manipulation of epigenetic marks, such as DNA methylation and histone modifications. Researchers have identified enzymes known as epigenetic modifiers that can add or remove these marks, thereby altering gene expression patterns. By targeting specific epigenetic marks associated with aging, researchers hope to rejuvenate cells and tissues and potentially extend healthy lifespan.

While epigenetic reprogramming shows promise as a potential anti-aging therapy, there are still many challenges and unanswered questions in this field. Further research is needed to fully understand the underlying mechanisms of epigenetic regulation and to develop safe and effective interventions for promoting healthy aging. Additionally, ethical considerations surrounding the use of such technologies in humans must be carefully addressed before epigenetic reprogramming can be widely implemented as a therapeutic approach for age-related diseases.

Human Endeavour

The ultimate example of the human endeavour of longevity is Brian Johnson, the multimillionaire who spends $2 million per year to maintain and improve his health. A rigorous attention to detail and lifestyle which is not for the faint-hearted. It involves consuming over 100 tablets per day including some medicines off licence and intensive monitoring. His project is called Blueprint – which is an “algorithm” for preserving his body.

Monitoring health has become essential in a personalised and predictive model of care. Wearables support the management of well-being and provide parameters for managing chronic disease.

Several variables beyond a healthy lifestyle are known to influence longevity. The sum of exposure to different xenobiotics and stress factors in the living and working environment accumulated during the individual lifespan, known as the exposome, affects both quality of life and longevity. 

High consumption of alcohol, drugs, and tobacco are some of the lifestyle variables known to increase significantly the risk of serious diseases and therefore both life and healthspan.

Exercise is one of the main factors that can affect longevity and reduces many major mortality risk factors, including hypertension, diabetes mellitus type 2, dyslipidemia, coronary heart disease, stroke, and cancer. Mortality decreases by about 30% to 35% in physically active subjects compared to inactive subjects.

Other factors that affect healthspan include diet and social interaction.

Conclusion

But amidst the excitement surrounding these enormous funding initiatives, advances in molecular mechanisms, a better understanding of human performance and new therapies, it's essential to tread cautiously. 

The quest for longevity undoubtedly raises profound ethical and philosophical questions that demand careful consideration. What are the societal implications of extending human lifespan? Will increased longevity exacerbate existing inequalities, or will it pave the way for a more equitable distribution of resources? And perhaps most fundamentally, what does it mean to lead a meaningful life in the face of infinite time?

Moreover, the pursuit of longevity inevitably intersects with the age-old quest for immortality. Is there a limit to how long humans can live, or are we on the brink of transcending the boundaries of mortality altogether? The prospect of eternal life raises profound existential questions, challenging our understanding of what it means to be human.

However, the quest to improve health span remains a critical mission. Most people desire a long, healthy life and are not necessarily worried about the length of life. Concentrating on managing chronic diseases better using personalised data and focusing on prevention will be an essential use of resources. We are now beginning to understand the fundamentals of human biology that will help us maintain good health for longer, thereby reducing the all important delta.