Reflections on the film, 'The Whale' (by a medical ethicist and a posturalist)

Reflections of a Medical Ethicist

Kim Junhyuk / Yonsei University Professor and Medical Ethicist

The film opens with a bus arriving in a rural village, then cuts to an online lecture. The lecturer in the centre is nowhere to be seen. It's not a programme we're used to seeing, but it's exactly what we've become accustomed to in the post-COVID-19 era: live online meetings. The camera pans closer and closer to the lecturer's screen, which is filled with black, and we soon see a gigantic figure in a state of agony, somehow trying to read an essay on the novel Moby Dick. This is the opening scene of the film The Whale.

Charlie, a 272kg man who has endured a number of untreated health problems, learns that he is about to die and tries to reunite with his daughter, whom he has kept at arm's length. He abandoned his wife and eight-year-old daughter for a life with a man of the same sex, and their relationship has never been restored since. The daughter seems intent on hurting everyone around her, and even her mother has given up trying to help her. With only a few days left to live, Charlie is determined to leave her daughter with at least a small measure of confidence that she can have a good life.

The play of the same name has been adapted by director Darren Aronofsky, and the film, like the novel Moby Dick, wrestles with the question of fate and redemption. And the film achieves its ending so brilliantly. Since this is probably not the best place to revisit the film's meaning (or since others have already done so brilliantly), I'm going to read the film from a medical humanities perspective here. First and foremost, the object that the film is confronting will be understood here as the disease.

As you may recall, Moby Dick is a long musing by the protagonist, Ishmael, who is caught up in Captain Ehave's vendetta against Moby Dick and observes it. At the end of the novel, Ehave throws a harpoon at Moby Dick, who is caught in the line and killed. The novel is often read as depicting a confrontation between nature and man, fate and choice, or brute force and will. It's hard to deny the falsity of Ehave's passion as he cries out in his dreams that Moby Dick, who could care less about humanity, is the devil plotting against him. So what is the film about? What is the protagonist fighting against?

Firstly, his body. Unable to quench his mental hunger, the protagonist's binge eating has resulted in massive weight gain and cardiovascular problems, and Charlie's inability to control his body has led him to try to make some sort of statement about his existence in the face of his final approaching death.

Perhaps because it's based on a play, the entire film takes place inside Charlie's not-so-spacious house. But when Charlie is alone and having an existential crisis (i.e., seeing his life denied to him), the music dazzles the viewer as if it were an ocean of waves. And it is. The room in 'The Whale' is the Pequod on its way to hunt Moby Dick. And, of course, the closest thing we see to a "whale" in front of us is the giant body of Charlie that fills the screen. Charlie is fighting against his own body. It's a narrative we're all familiar with. We've all been there, battling our own bodies at one time or another: dieting, quitting smoking, getting sober, staying up at night with drooping eyelids. If you think of the whale in "The Whale" as a body, the film is simple. It's about a man binge eating and battling a cardiovascular disease that's trying to kill him.

But if you understand it that way, there's no point in watching this film, because there are so many stories of battles with the body in fiction, non-fiction, and film, and it's not like this film is particularly convincing in that regard. Plus, the main character doesn't really battle the body. Plus, I was sobbing at the end of this film. But if that's what this film is about, then I'm a weirdo.

Let's take a different approach. For this approach, we need a new concept of social disease.

The Whale won two Academy Awards for Brandon Fraser's performance as Charlie, and many overlapped the film with Fraser's own life, where he was abused by the film industry as a young, handsome actor, then divorced and raised a son on the autism spectrum.

What is social illness?

As we outlined last time, there is a problem with illnesses that have a social dimension, as opposed to illnesses that have a biological dimension or illnesses that have a personal, experiential dimension. On the one hand, there are cases where society exacerbates a disease or condition. The most common example in everyday life is the illness caused by overwork, and by extension, overwork death. In a social or professional environment that does not guarantee the individual sufficient rest and demands constant tension, a predisposition he has, whether genetic or otherwise, is aggravated and he dies of an acute heart attack. On the other hand, there is the phenomenon of disease manifesting itself differently in different population groups due to differences in social conditions. In general, many diseases are more prevalent and more severe in lower-income groups than in higher-income groups, and in slums than in richer areas. An easy example is tooth decay or gum disease. Obviously, tooth decay and gum disease are more prevalent in low-income communities and slums.

On the other hand, some things become ill because of social circumstances or factors. Society decides what is and isn't a problem, and when it manifests itself in an individual's body, it is labelled as a disease. Take eugenics, for example. As you may know, eugenics is the effort to enhance the genetic disposition of an entire population (usually the people of a country). Eugenics does this in two ways. There are other problems, but the biggest one is that society defines what constitutes "superior" and "inferior". When Nazi Germany decided that the blood of Jews and Gypsies was inferior, ethnicity became a social disease.

The same thing can be said about disability or genetic disease. A disability may make an individual's life uncomfortable. But are people with disabilities inferior to people without disabilities?

No. Nevertheless, when society identifies certain ethnicities, disabilities, or even languages or abilities as "inferior" and attributes them to individual problems, society makes these factors sick on unclear grounds. This is also a social disease. I will call this social illness "wu-huan" (憂患) because the Chinese character wu (患) means both trouble, illness, and calamity, and the Chinese character wu (憂) means illness, pain, and suffering. Social sickness refers to the suffering of the body and mind caused by problems beyond the individual level, by catastrophes, and we suffer because of them.

Harpooning a world of hate and exclusion

In 'The Whale', Charlie is ostensibly unable to control his appetite and is beyond the point of being described as morbidly obese. But why did he get there? 

It's because a society that didn't tolerate his lover drove her to her death. His love could not save his lover. Because his relationship with his lover was considered an unacceptable illness. His life had become an illness.

Thus, the whale the film confronts is not Charlie's biological body. The Moby Dick of The Whale is a world that makes him an object of disgust and exclusion. Like Moby Dick in the original novel, the world is not interested in the individual. It doesn't deliberately try to kill him, it doesn't have a grudge against him or a spiteful plan to push him into a pit, but it's that indifference that kills us. Someone is drowned in the great waves of the world, and he is left alone. Our striving for life becomes futile in the face of that injustice, that impartiality that does not make the stronger suffer more, that does not protect the weaker. And so, even though we know that AHAB is an unbeatable opponent, we can't help but cheer him on when he strikes the harpoon of hate.

The film climaxes with Charlie and his daughter together picking up Ehave's harpoon and hurling it into the world (of course, there are no harpoon, no fight, or even a violent movement in the film). And we see through The Whale. The world will prevail. Small gestures by individuals can do little more than put a tiny dent in its enormity. But those scratches will one day bring down the world, the great whale. It's not easy to do anything about the enemies that surround us. From the distant 4-3 to the nearer Itaewon, from the broader Japan that defined Korean blood as inferior to the narrower practices surrounding genetic engineering, the world, in its indifference, robs the individual of his rights and suffocates him. But we know. As we hurl our seemingly futile harpoons, those bottles, Wu Hwan, will one day fall.

Reflections of a Posture Expert / Eam Taekyoung

Types of social stress

In addition to overwork, economic class, and social prejudice, factors that contribute to social stress include overly self-centred individuals and groups, competing groups, legislation and organisational cultures that do not reflect social change, and sudden changes in the social environment (since the mid-1990s (IMF crisis), South Korea has seen a sharp increase in suicide rates, finally overtaking Japan), The universal consciousness of groups that use the individual as a tool to achieve group goals, and the endless competition among various groups that stems from evolutionary humans not having the genetic systems to control over-satisfaction (surplus).

I believe that a more fundamental social stressor than the ones listed above is "postural deformity due to rapid sedentary socialisation". There are so many variables that affect posture that it is very difficult to approach analytically. In addition, the stress caused by sedentary posture is an underlying stress that everyone experiences, is universally recognised as an individual problem, and a direct causal relationship between posture and stress is not readily apparent. As a result, there is no group of people who have systematically and scientifically studied the relationship between posture and stress. However, I believe that posture is a very personal stress, but it is also a social stress because it is a stress that everyone experiences, and this stress is the underlying energy that fuels the universal aggression of modern people.

Stress in Paleolithic humans

Our bodies and minds have evolved to adapt to the hunter-gatherer lifestyle of the Paleolithic. A hunter-gatherer lifestyle means that most of our daily activities take place in the great outdoors, where we are exposed to considerable risk. You might encounter wild animals or venomous plants and animals. 

So if you're faced with a situation that could threaten your life, you have two choices: fight or flight, and in both cases you need to be physically strong. So it's a very strong physical and mental tension. In the Paleolithic period, these highly stressful situations were common enough that they developed appropriate coping mechanisms. During this time, the ability to run was one of the most important means of survival, so it's likely that our bodies were optimised for running. However, modern humans still have this Paleolithic running optimised body. In the photo below, you can see that the centre of gravity of the head is at a tilt of about 12 degrees when looking straight ahead, and the average marathon runner's spine is also at a tilt of about 12 degrees.

Stress in the modern world

The universal stress that modern humans experience is much different than that of Paleolithic humans. 

First, the most common stress in modern humans seems to be physical stress from the bending moments of the spine. This stress seems to be a constant, not a variable, that is unavoidable for anyone who spends time sitting. Since most of us lead sedentary lifestyles, our muscles must be tense to support the bending moments caused by our downward-facing posture. 

However, the low level of tension in these muscles makes it very difficult to recognise the problem, and postural deformities continue to build up over a person's entire life. So slowly and steadily, their impact seems to grow, making it natural for almost everyone to have one or two ailments in the second half of life.

Secondly, whereas Paleolithic humans lived a life with an approximate 50:50 relationship with nature and the people around them, modern humans seem to live a life with an approximate 50:50 relationship with nature and the people around them. In general, modern people have become less connected to animals and nature and more connected to themselves and the people around them.

In the Paleolithic era, there was always a powerful threat of life and death in the great outdoors, and the stress caused by that was very powerful, so the stress caused by relationships with other people was probably relatively weak and not continuous (?). However, modern society has conquered all of the stressors caused by nature, so it can be seen that stress caused by internal problems and relationships with others has become important.

This means that Paleolithic humans had a strong stress response that was honed by the threats they faced from the great outdoors, so the stress of interpersonal relationships would have been manageable. However, for us modern humans, it is quite possible that the stress of our current lives, of which the stress of our relationships with others is a part, is the most powerful stress we experience.

To summarise. We modern humans still have systems that are well suited to managing the characteristics of the Paleolithic human body and mind, but Paleolithic humans were generally exposed to strong but short-lived stresses, and modern humans are generally exposed to weak but long-lived stresses. In other words, while Paleolithic humans lived lives characterised by "powerful but short-lived stress", modern humans generally live lives characterised by "psychologically powerful and very long-lived stress", which is weaker in absolute stress intensity compared to Paleolithic humans. Unfortunately, humans have not evolved adequate coping mechanisms to deal with this kind of 'sustained low-intensity stress' in the distant past. 

The paradox here is that the safer society becomes, the more intense the psychological stress people experience. This may explain why our society is becoming safer, but younger people are finding life more challenging.

The Butterfly Effect of Sedentary Socialisation

Stress in the modern world is mainly caused by mild but persistent stresses (such as prolonged sitting with a downward gaze and emotional labour), and modern people are increasingly exposed to the effects of these stresses due to the progress of digital socialisation. Sitting for long periods of time with a downward gaze seems to be the main cause of mild but persistent stress in modern people, and the secondary cause of increasing aggression and depression.

Nowadays, people in general, whether young, middle-aged or elderly, are spending less time playing sports and more time in sedentary activities such as studying, playing games and using smartphones, so the amount of time spent in a slouched position continues to increase. 

Slouching can lead to unrecognised micro-pain, which shifts brain activity from the 'pain circuitry' to the 'emotional processing circuitry', which can lead to an increase in violent tendencies. According to Dr Srinivas Pillay of Harvard University, mild low back pain is the second most common cause of disability in the United States, and more than 80 per cent of Americans will experience it in their lifetime. He also notes that when pain persists, the associated brain activity shifts from "pain" circuits to circuits that process emotions, and that emotions such as anxiety often stem from chronic back pain, making it much more difficult to regulate.

* Mechanisms of appetite in sustained low-intensity stress:

- Paleolithic: turbo mode (hunting, running) --> sympathetic nerve activation (heart, lungs, eyes) --> high energy expenditure --> energy replenishment through appetite.

- Modern: Stress mode --> Sympathetic nerve activation (activation of heart, lungs, eye function) --> Energy expenditure is not high --> Energy replenishment through appetite --> Obesity

* Disease-causing mechanisms of continuous low-intensity stress: Continuous stress --> depression --> dysautonomia --> decreased breathing rate --> poor circulation --> poor blood supply to some areas of the body and decreased physical activity --> calcification of unused muscles --> postural deformity and accelerated deterioration of body parts --> disease occurs in normally weak areas.

* Transition mechanism of persistent low-intensity stress to aggression: mild but persistent physical/mental stress --> low-intensity pain --> stimulation of pain circuitry --> stimulation of emotional circuitry --> transformation of perceptions of difference into feelings of intolerance --> accumulation --> manifestation in aggressive behaviour. 

Underlying causes of ageing

The paper, 'Summary of the Copenhagen Conference on Ageing 2022', states that  

"Genomic instability, telomere attrition, epigenetic changes, mitochondrial dysfunction, loss of proteins, deregulated nutrient sensing, cellular senescence, stem cell depletion, and altered cell-to-cell communication were the 10 hallmarks of aging proposed by López-Otín and colleagues in 2013. The proposal of these features of aging has been instrumental in guiding and driving research into the biology of aging. Nearly a decade of in-depth exploration of aging research has led to the formulation of new features of aging, including autophagic damage, microbiome perturbation, altered mechanical properties, junctional dysregulation, and inflammation. The convergence of 'old' and 'new' features of aging provides a more comprehensive explanation of aging and age-related diseases, which can shed light on the study of interventions and treatments to achieve a healthy, happy and productive life for the elderly."

A key consideration in research into the causes of chronic diseases is that modern humans, as well as those of the past, are still born with bodies built for running, but have rapidly become sedentary through the Industrial Revolution, the internet and the popularisation of smartphones, and yet the medical community seems to have failed to include this as a consideration at all.

I believe that the genomic instability, telomere attrition, epigenetic changes, mitochondrial dysfunction, loss of proteins, deregulated nutrient sensing, cellular senescence, stem cell depletion and altered cell-to-cell communication, autophagy damage, microbiome disruption, altered mechanical properties, junctional dysregulation and inflammation that have been identified as causes of aging are all directly or indirectly related to the problems caused by living in a sedentary society with a body fit for running. 

Due to a sedentary lifestyle, "progressive postural modifications" and (or) "constant tension in some muscles" appear to contribute to decreased autophagy, neurodegeneration, immune ageing, decreased cell motility, decreased cell-to-cell communication, cell stiffness, and loss of elasticity. 'Progressive modification of posture' leads to gradual atrophy or crushing of blood vessels, nerve and lymphatic vessels. 'Constant tension in some muscles' can lead to progressive atrophy of cellular metabolism. This 'gradual' change can be seen as ageing.

The reason why chronic oxidative stress in immortal cell lines leads to telomere shortening, impaired growth, and genomic instability, while acute stress has little effect, is that our stress management mechanisms are well-established to deal with "high-intensity, short-term stress," but virtually nonexistent for "low-intensity, sustained stress," in order to respond well to attacks from threatening animals. This is because modern humans still have bodies that have evolved to cope with frequent exposure to life-threatening predators in the Paleolithic era. 

Mitochondria are responsible for converting food into energy that the cell can ultimately use. The emergence of mitochondrial transplantation as a new treatment for dementia and the correlation between aerobic exercise and mitochondrial volume seem to offer a new interpretation of the causes and remedies of dementia. It is worth noting that the cause and solution of dementia can be interpreted as follows. 

Dementia is a degenerative disease. As a result of the Industrial Revolution, physical activity, such as running and walking, has declined in relation to the sudden increase in life expectancy since the 1950s. In addition, people generally lose muscle mass after about 40 years of age, which leads to a generalised and intensified slouching posture, especially with the head protruding forward, after about 50 years of age. This makes it easier for the blood vessels that pass through the neck area to become compressed or constantly stiff. This leads to a deterioration in the quantity and quality of blood supply to the brain. It"s a degenerative condition.

To prevent dementia, the most important thing is to avoid forward bending of the neck in the average daily posture. Next, it"s important to reduce activities that require the brain to constantly focus on something, as fatigue builds up when the amount of breathing is low compared to the energy used. Breathing is one of the reasons why writers have a shorter lifespan than people in other professions, which can be very stressful.

Conclusion

As a posture expert, I believe that many of the physical and mental illnesses, ageing, depression, social aggression, etc. of modern society are all derived from "posture-induced social stress," which is caused by the rapid transformation of global society into a sedentary society. Therefore, it seems that medical scientists need to study and analyse the fact that we modern humans still have a body that has evolved to suit the Paleolithic way of life [a way of life based on hunter-gatherer life, involving activity (body), stress and food], but live in a significantly different modern environment, as the first and most fundamental factor to consider. The current focus on the micro-world of genes and the like is very worrying. We should not lose sight of the fact that our bodies are integrated, networked, mega-variable functions. 

If we don't do enough to address the common postural stresses of modern life, it's increasingly likely that I or my family members will take over the role of Charlie from The Whale in real life. 

When the film ended, I thought of the poet Arthur Rimbaud. Perhaps Charlie is the reincarnation of Rimbaud...

#Reflection #film #TheWhale #medical #ethicist #posturalist #Charlie #MobyDick

Spring, the most challenging time of year for the body.

 

Spring (March to May in Korea): lowest humidity of the year, largest temperature differences, and increased sunlight --> the most challenging time of year for the body.

Low humidity: the air contains less water vapour, so you breathe harsher air, which increases the strain on your respiratory system.

High daily temperature difference : the body's systems have to work harder to adapt to fluctuating temperatures throughout the day.

Increased sunlight: longer days and more sunlight can disrupt your circadian rhythm and cause sleep disturbances.

Seoul, South Korea - Climate & Monthly weather forecast (weather-atlas.com)

A critique of Michael Sandel's Democracy's Discontent

 How does capitalism ruin democracy? (pressian.com)

Columnist Kim Chang-hoon | 2023.04.22. 

I read a book by philosopher Michael Sandel for the first time in a long time. The original English title is <Democracy's Discontent>. It's an unusual title. Sandel believes that American democracy has deviated from the norm. The United States has been a democracy for a long time, but if you look back at events like the Capitol riots, it's clear that American democracy is in serious trouble. The prosecution of Trump shows that there is an irreconcilable rift in American society. How did we get here? Sandel explores how democracy has become so corrupted.

Sandel identifies two widespread grievances in American society. The first is that "people are losing control of the forces that govern their lives, both individually and collectively." The second is a perception that "the moral bonds of the community are loosening." Sandel attributes this discontent to the American public's failure to critically reflect on what he calls "public philosophy". Public philosophy refers to "the political theories that are embedded in the behaviours we practice - the set of assumptions about citizenship and freedom." In other words, public philosophy is the view of political philosophy that is tacitly endorsed by society and serves as the basis for individual behaviour. 

We think of American democracy as a monolithic concept that has been around for hundreds of years, but that's not the case. Sandel believes that American democracy has strayed too far from its initial ideology of republicanism. Republicanism is the idea that the participation of virtuous citizens is more important than the freedom of ownership and personal choice. Sandel's favourite politician is Thomas Jefferson, the founding father and third president of the United States. He begins his story with Jefferson.

In the United States, freedom has been an important ideology from the beginning. It also required a certain kind of material foundation to maintain it. Thomas Jefferson, a founding father and third president, opposed the promotion of big manufacturing on the grounds that an agrarian way of life created moral citizens fit for self-government. His reasoning was different from today's: large-scale manufacturing undermines independence, a prerequisite for republican citizenship. Jefferson believed that citizens whose independence had been eroded by manufacturing conglomerates would not be able to exercise the self-governance at the heart of American democracy. "The idea that liberty requires self-government, and that self-government, in turn, depends on civic virtue, is at the heart of republicanism," Jefferson thought. He was not alone in this view. Benjamin Franklin, an inventor and thinker, also believed that "only a moral man, with a proper education, is capable of enjoying liberty". This was the common sense of the educated at the time.

The republican model of prioritising the lives of the people, which Sandel calls the "political economy of citizenship", was rejected by another Founding Father, Alexander Hamilton. Hamilton established federal fiscal policy and sought to revive large-scale manufacturing. Hamilton was in favour of subsidising businesses. For the Republicans, this was a dangerous policy that would lead to rampant corruption. The republicans of the day considered the republican ideal to be a community of self-governing farmers, not tenant farmers. The American democracy that Tocqueville admired was a participatory democracy practised in small towns. But a tidal wave of capitalism washed over the country. The Jeffersonian model was swept aside and society was increasingly transformed by Hamilton's vision. Material growth became the only thing that mattered.

Even in the midst of change, many agreed that economic independence was an essential prerequisite for citizenship. Economic independence was not the same as independence as we know it today. Throughout the 19th century, wage labour was denounced as a system that undermined human independence, often referred to as wage slavery. Commentators like John Caldwell Calhoun scorned the capitalist wage system in the North as worse than slavery. They denounced the lifetime employment and basic welfare provided to slaves as non-existent for Northern wage earners. George FitzHugh, a Southern antislavery theorist, said. 

"You [Northern entrepreneurs] are slaveholders, but you are slaveholders who do not fulfil the duties of slaveholders." 

Economic independence meant homesteading. At the time, there was considerable popular opposition to wage labour. Psychological resistance to wage labour had to disappear in order for capitalism to flourish. Pro-capitalist wage labour advocates began to discard the civil concept of "free labour" after the Civil War, which referred to the right to work without being subject to bondage. As a civil right, "free labour" was eventually reduced to the freedom to choose one's work. The concept of "voluntarism" was introduced to replace "free labour". Labour was now packaged as the product of a voluntary contract between employer and employee. Pro-capitalists touted these labour contracts as being in line with existing notions of freedom. The Lochner case of 1895 was the catalyst. Lochner, a New York City baker, was fined for violating a New York state law that stated that the workweek could not exceed 60 hours in a 10-hour day. He argued that the law was not coercive and was a mutual agreement with his employees. The Supreme Court sided with Lochner and ruled that the New York law violated freedom of contract. This was the turning point in which freedom of contract was declared to be a more important value than a full and independent life.

The idea of "voluntary contract" in labour was expanded after World War II into a "voluntary libertarianism". This view of freedom stems from the voluntary self-image. According to Sandel, the voluntarist self-image is "the idea of an independent self that is free to choose whatever it wants to do." This view of the self has been mainstream since the mid-20th century. Sandel believes that the voluntarist self-image has led to valuable achievements such as the welfare state and the expansion of individual rights. This view of self and freedom resonates with liberalism.

Has this self-image, view of freedom, and liberalism made Americans happier? Sandel is adamant that it hasn't. Says Sandel. 

"Despite the expansion of individual rights and benefits over the past few decades, Americans' control over the factors that shape their lives has actually declined." 

"Paradoxically, the triumph of the voluntary libertarian view has occurred in the midst of diminishing individual control or influence." 

Sandel even goes so far as to claim that 

"The difficulties facing liberal democracy in the United States today may not be the result of specific frustrations, but rather of a lack of the voluntarist self-image that underpins liberal democracy." 

The voluntarist self-image assumes an unattached self in favour of community. By focusing on these individual attributes of human beings, Sandel believes that liberalism neglects another human attribute: community.

Sandel criticises liberals for limiting power to proceduralism. When political power fails to control capital power, society breaks down. In Sandel's words. 

"The rise of right-wing, anti-immigrant populism is usually a sign of the failure of progressive politics. When liberals fail to protect people from powerful groups by keeping economic power democratically tied to them, people look elsewhere." 

Sandel believes that liberalism based on a voluntary self-image has ultimately failed American society. Republics break down when political power becomes mired in procedural legitimacy.

The vision of Sandel and other communitarians is based on a longing for life in a town. His preoccupation with republicanism and communitarianism is rooted in town life in the early days of the founding, when republican sensibilities were alive and well. The bonds of community are fundamentally incomprehensible without the space of the town. According to Tocqueville, the town, the heart of American self-government, was only two or three thousand people in size. Here's what Tocqueville had to say about the size of the town. 

"On the one hand, it is not too large, so that the interests of its inhabitants will not be in conflict; on the other hand, it is not too small, so that men capable of presiding over its affairs can always be found among its citizens." (Democracy in America by Alexis de Tocqueville, published by Han Gil.)

Let's look at the writings of another communitarian philosopher, MacIntyre. His book is full of romanticised longing for the pre-modern era. McIntyre writes 

"For liberal individualism, the community is merely a stage on which every individual pursues his or her own self-chosen idea of the 'good life'. (In the ancient and medieval view, by contrast, the political community not only requires the practice of the virtues in order to maintain itself, but it is the task of authoritative adults to raise children into virtuous adults." (The Loss of Virtue) 

In other words, while modern people are preoccupied with their own good, ancient and medieval people not only tried to live virtuous lives, but also taught their children to live virtuous lives. McIntyre proposes a communitarianism based on virtue as an alternative to liberalism based on individualism. It sounds good, but is it possible?

Ethical philosopher Hwang Kyung-sik disagrees with the communitarians' proposal to build a community based on virtue in his article, "The Correlation between Moral Systems and Social Structures. Here's what Hwang has to say about the relationship between morality and social structure. 

"A moral system, no matter how reasonable and desirable it may seem in itself, is powerless and meaningless as a social ethic if it cannot function properly as a practical guide, that is, if there is a defect in its practical applicability or realisability." 

Recreating traditional ethics and virtue ideas in the modern era requires social and philosophical reflection on the conditions of modern society. His words are soft but firm. Hwang says that it will not be possible to create a virtuous community based on small communities without assuming a revolution.

The decline of the traditional republican virtue ethic of the Gemeinschaft, a community based on kinship and connection, cannot be attributed solely to liberalism. Rather, it would be more accurate to say that the rise of a large and anonymous society led to the loss of the traditional virtue ethic, the republican ethos, and the introduction of individualistic liberalism to replace it. Kant, Mill, and Rawls are the representative thinkers of liberalism who captured this society. In other words, liberalism is an ethical system that responds to huge changes in the substructure. Hwang Kyungsik says 

"Unless a fundamental reform of the structure of modern society is premised or a transformation of the socio-economic system is possible, the ethics of rules and obligations (liberal ethics - my note) will have to exist as the leading moral system of modern society, especially as the substructure and basic order of character and virtue ethics." 

The argument is that a liberal ethic is inevitable in a complex society like the modern world.

Sandel encourages republicanism to overcome the social unrest that capitalism creates. Sandel's attachment to republicanism leaves something to be desired. It doesn't go beyond the red lines set by the ruling class. In his words. 

"Keynes's insights are both liberating and sobering. His insight that politics comes first is the most liberating of all." 

His vision stops short of calling for a republican politics that has the guts to reintroduce Keynesianism in place of neoliberalism. America has tried Keynesianism and neoliberalism. Both have failed. America is now in a state of actual civil war.

Thinker Nakcheong Baek offers a different perspective. In a conversation with Yongok Kim, Baek says that the framers of the US Constitution "had a clear intention not to have a democracy". The separation of powers, bicameralism, and indirect presidential elections were created with that intention. They created a system in which the wishes of the people were structurally distorted through various devices. Left unchecked, any attempt at reform is bound to result in an oligarchy. As long as American democracy maintains the mechanisms that ultimately lead to oligarchy, it is impossible to build a political force that can overcome economic power. Philosopher Yongok Kim's critique of democracy is even more radical. "It is important to get away from the violence of the language of democracy," he says. "It is important to break free from the violence of the language of democracy," he says.

Can Sandel's republicanism shed a glimmer of light on the decline of democracy in the United States and around the world? I don't think so. But I think Sandel's proposal for a virtue-based community is a valuable one. I believe that Joseon, a "precocious modern state" as indigenous theologian Lee Eun-sun calls it, lasted for 500 years because it orientated its intellectual cognitive class of Yangban to the ethical ideology of Sunghwa.

After reading the book, I feel like this. Democracy is so hard to go along with capitalism.

Contemplation/Eam Taekyoung

Modern society is a global organism. Not only living organisms but also social organisations can be called organisms if they have three capabilities: independent self-replication, independent energy conversion, and independent homeostasis. The modern nation-state is not an organism, but rather a sub-organism of an organism, because it lacks these three functions.

Modern global society is a hydra-organism that is economically, socially, and culturally connected as a single body but politically has many heads. The underlying causes of many of the problems of global society are the problems caused by the structure of this hydra-organic society.

The current problem facing the United States may be due to the fact that it has reached the final stages of aging because it has received surplus calories from other countries, causing it to mature more quickly. This seems to be a consequence of the principle of aging, one of the six main principles of organismal evolution.

Democracy as a reflexive political system of imperialism seems inevitably to be transformed into a political system suitable for the emergence of a global organic society. The coming political system will be found to reflect the principle of optimal efficiency, the principle of imitation, and the principle of metacognition as it dissolves the hydra society.  

The six main principles of organismal evolution

1. The Principle of Optimal Efficiency 

The evolutionary direction of higher life was to minimise the moment (force to rotate around a point) generated by the body during energy acquisition activities. This can be described as the pursuit of optimal efficiency in energy acquisition/consumption. Animals have continued to optimise in the direction of uprightness for walking and streamlining for flying and swimming. Note that "pursuit" here does not mean pursuit as directed by will. When we look back at the results of the interaction of natural selection and rare leaps (mutations), we observe trends that can be interpreted as "pursuit".

2. The principle of instability

Instability is the driving force behind the evolution of life and social organisms (organisations, nations, etc.). "Irreversibility leads to instability, instability gives rise to self-organisation, and self-organisation gives rise to life," said Nobel Laureate in Chemistry Ilya Prigozhin. By the same principle, desire (irreversibility) leads to chaos (instability), chaos (instability) leads to the will to change (self-organisation), and the will to change (self-organisation) leads to new societies (life).

3. Principles of Aging

The rate of "excess energy accumulation" and "deepening energy distribution imbalance" is the rate of aging of individual life or individual social organisms. According to Harvard biologist Bernd Heinrich, "Consuming a surplus of calories means growing faster, maturing faster, and living shorter." 

4. The principle of imitation

The structure of human society has evolved and will continue to evolve towards a more sophisticated mimicry of the human body and mind (brain)! Social structural evolution is a particle avatarisation of humans, and the metaverse can be seen as a wave avatarisation.

5. Principles of Metacognition

Every organism has its own path to optimal efficiency, but it can be categorised into two paths. The first one is to obey the will of selfish genes (blueprints) (survival and reproduction). The second path is to go beyond the will of the genes through metacognition. It defies the second law of thermodynamics. Socrates' words, "Know thyself!" can be seen as the formal starting point of metacognition and social evolution.

6. The principle of connection

Humanity has been connected in proportion to the development of transport and communication. As transport and communication have advanced, the scope of the "social we" in human society has expanded and connectivity has deepened. It will continue to do so!

Causes and Solutions of Justin Bieber's Ramsay Hunt syndrome

 Justin Bieber: Boy with Ramsay Hunt syndrome thanks star

17 March 2023

An eight-year-old boy with the same rare condition as Justin Bieber has said the star's diagnosis would help raise awareness.

Ethan, from Newport, and Bieber both have Ramsay Hunt syndrome (RHS), which, among other things, can cause facial paralysis.

Ethan said he wished Bieber well, and that him going public had made it "easier to talk about" the condition.

A big Bieber fan, Ethan has had the condition since he was six years old.

RHS is when a shingles outbreak affects the facial nerve near someone's ears, resulting in paralysis of parts of the face as well as blisters in the ears and on the roof of the mouth.

Justin Bieber had to cancel his world tour this month due to ongoing issues with the condition.

Contemplation/Eam Taekyoung

According to the article above, Ramsay-Hunt syndrome (RHS) is a condition in which an outbreak of shingles affects the facial nerve near the ear, causing partial paralysis of the face and blisters around the ear and roof of the mouth. It is also known that shingles is caused by the varicella-zoster virus (VZV), which causes chickenpox in childhood and then remains asymptomatic around the nerves, but when immunity to the varicella-zoster virus wanes, it travels up the nerves and causes a rash on the skin, causing severe pain.

Bell's Palsy appears to be caused by a common virus other than the varicella-zoster virus that paralyzes one side of the face. 

Causes

Now, I will give my opinion on the causes and countermeasures of Ramsey-Hunt syndrome and Bell's palsy.

I believe that these diseases are caused by postural deformities that cause the spinal system to curve to the side. Postural habits that lead to a constant lateral curvature of the spinal system in our daily lives seem to be a key factor. This lopsided posture can cause constant compression of the nerves and blood vessels against the skull, which can lead to deterioration of the nerves and blood vessels, and this deterioration seems to create an environment in which the virus can thrive.

In our body, nerves and blood vessels around the neck and skull are more concentrated on each side than in other parts of the body. If a person with a lateral slouching posture is exposed to continuous stress, he will be more likely to develop Ramsey-Hunt syndrome or Bell's palsy.  Not everyone will develop these diseases if the requirements of lateral slouching and continuous stress are met, but it is likely that those who do develop them will have had both.

Solutions

The solution is to eliminate the causes. You'll need to improve your posture habits and remove yourself from environments that expose you to continuous stress.

 #Causes #Solutions #Justin #Bieber #Ramsay #Hunt #syndrome #Bell's #palsy

Contemplation About the 'Summary of the 2022 Copenhagen Aging Conference'

 

New hallmarks of ageing: a 2022 Copenhagen ageing meeting summary

Tomas Schmauck-Medina, 1 ,* Adrian Molière, 1 ,* Sofie Lautrup, 1 Jianying Zhang, 1 Stefan Chlopicki, 2 Helena Borland Madsen, 3 Shuqin Cao, 1 Casper Soendenbroe, 4 Els Mansell, 5 , 6 Mark Bitsch Vestergaard, 7 Zhiquan Li, 3 Yosef Shiloh, 8 Patricia L. Opresko, 9 , 18 Jean-Marc Egly, 10 , 11 Thomas Kirkwood, 3 , 12 Eric Verdin, 13 Vilhelm A. Bohr, 3 , 14 Lynne S. Cox, 15 Tinna Stevnsner, 16 Lene Juel Rasmussen, 3 and Evandro F. Fang 1 , 17

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Abstract

Genomic instability, telomere attrition, epigenetic alterations, mitochondrial dysfunction, loss of proteostasis, deregulated nutrient-sensing, cellular senescence, stem cell exhaustion, and altered intercellular communication were the original nine hallmarks of ageing proposed by López-Otín and colleagues in 2013. The proposal of these hallmarks of ageing has been instrumental in guiding and pushing forward research on the biology of ageing. In the nearly past 10 years, our in-depth exploration on ageing research has enabled us to formulate new hallmarks of ageing which are compromised autophagy, microbiome disturbance, altered mechanical properties, splicing dysregulation, and inflammation, among other emerging ones. Amalgamation of the ‘old’ and ‘new’ hallmarks of ageing may provide a more comprehensive explanation of ageing and age-related diseases, shedding light on interventional and therapeutic studies to achieve healthy, happy, and productive lives in the elderly.

Keywords: hallmarks of ageing, neurodegeneration, healthspan, longevity, autophagy

Eam Taekyung: I would like to present my opinion on what is discussed in this paper from the perspective of a posture expert in each of the items below.

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INTRODUCTION

The definition of nine cellular and molecular hallmarks of ageing by López-Otín and colleagues in 2013 [1] provided a contextual framework to guide future ageing research. These hallmarks comprise: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Recently, these hallmarks have been criticized for being insufficient in serving as a causative paradigm of ageing [2]. Importantly though, they have recently been shown to map to age-related diseases [3]. To address this and to explore potential new hallmarks, a research symposium “New Hallmarks of Ageing” was held in Copenhagen (Denmark) on the 22nd of March 2022, focusing on novel findings and the recontextualization of the nine hallmarks of ageing. This included the discussion of new advances and the future of the field of ageing research.

The symposium contained presentations from the keynote speakers Professors Yosef Shiloh (Tel Aviv University), Vilhelm A. Bohr (National Institute of Ageing), Lynne Cox (University of Oxford), Thomas Kirkwood (Newcastle University), Jean-Marc Egly (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Patricia Opresko (University of Pittsburgh), Erik Verdin (Buck Institute for Research on Ageing) and selected short talks from young and senior researchers, and ended with a panel discussion with some of the key speakers of the event.

The panel stressed the importance of progress in the field, as ageing is the primary risk factor of many major human diseases. It was highlighted that increasing average lifespan over the last decades is one of the most remarkable human accomplishments, but that this success has led to a different, challenging problem, namely the ever-increasing number of chronically ill patients suffering from age-related diseases, and the resulting toll on individuals and society. Understanding the mechanisms of the ageing process will therefore be pivotal to treat the root cause of multiple age-related diseases.

Eam Taekyung: In a study related to the causes of chronic diseases, not only old humans but also modern people are still born with bodies suitable for running. However, through the Industrial Revolution, the popularization of the Internet and smartphones, modern people have come to live in a rapidly sedentary society. The medical community has yet to include this point in the category of consideration, even though it should be considered at the core. 

Genomic instability, telomere consumption, epigenetic changes, mitochondrial dysfunction, protein loss, deregulated nutrient detection, cell aging, stem cell depletion and intercellular communication changes, autophagy damage, microbiome disturbance, bonding control disorders, and inflammation were cited as causes of aging. However, it is thought that they are directly or indirectly related to the problems that arise because they all live in a sitting-centered society with a body suitable for running.

The panellists emphasised that only taking a limited number of defined hallmarks into account might also halt progress on processes relevant to ageing but not currently defined as hallmarks. The panellists thereby discussed the inclusion of new hallmarks to the current list (Figure 1), based on new evidence underpinning their role in the ageing process. Some discussed additions were compromised autophagy, dysregulation in RNA splicing, inflammation, loss of cytoskeleton integrity, and disturbance of the microbiome (Box 1).

Figure 1

New hallmarks of ageing. The figure enumerates the original hallmarks of ageing plus the five new proposed hallmarks that were discussed in the symposium. To qualify as a hallmark, the processes should change with biological age not simply in a correlative manner, but have a causal role. Hence interventions that address the hallmarks should, at the very least, halt further detrimental aspects of ageing, and preferably improve phenotypes associated with ageing.

Box 1

New hallmarks of ageing.

Compromised autophagy is observed in numerous ageing conditions including neurodegeneration and immunosenescence [8, 9]. Importantly activation of autophagy can increase mouse lifespan [10], and even improve immune response to vaccination in older humans by overcoming immunosenescence [11]. While originally considered under hallmark ‘altered proteostasis’, autophagy regulates a number of other hallmarks of ageing such as DNA repair and nutrient sensing/metabolism [12], and hence it was proposed to be categorised as an integrative hallmark.

Dysregulation of RNA processing has been noted in human ageing population studies [13] while interventions that appear to reverse senescent phenotypes act at least in part by restoring youthful patterns of splicing factor expression [14]. Similarly, alternative polyadenylation of mRNAs, already known to contribute to cancer [15] is altered with ageing and may contribute to senescence [16]. Such changes in RNA processing add an additional layer of gene expression control over those of genome integrity, transcriptional efficacy and epigenetic regulation that are already known to change during biological ageing.

Microbiome disturbances: recent advances in next generation sequencing technologies have allowed the identification of notable changes in the gut microbiome with age [17], pointing in particular to shifts in microbial populations and loss of species diversity. Together with age-associated loss of structural integrity of the gut and other barriers (e.g. blood brain barrier), this shift in microbial populations can drive inflammation.

Altered mechanical properties applies both to cells and to the extracellular milieu. For example, fibroblast senescence is accompanied by a major change from a mobilizable pool of actin that can be readily polymerised and depolymerised during cell motility, to stable stress fibres of f-actin anchored through focal adhesions to the substrate [18], which is particularly marked in cells from patients with premature ageing syndromes [19] and which is likely to impact on cell motility and cell-cell communication. Motility changes are of major relevance in innate immune system ageing, where neutrophils from old donors cause significant tissue damage on migration to sites of inflammatory signalling; modification of the small G protein signalling pathways that regulate such cytoskeletal motility through treatment with statins greatly improves older neutrophil action in vitro and results in highly significant increases in 6 month mortality follow up from older adults admitted to the ICU with pneumonia [20]. The nucleoskeleton is also altered during ageing, with the nuclear lamina becoming destabilised, with concomitant extrusion of chromatin into the cytoplasm as CCFs which trigger the SASP in senescence [21]. Importantly, the nuclear lamina is highly defective in Hutchison-Gilford progeria [22] and clinical trials of farnesyl transferase inhibitors that restore NE integrity increase patient lifespan [23]. Finally, extracellular matrix also changes with ageing, which greatly alters cell behaviour [24]. Increased rigidity and loss of elasticity, for example arising through glycation cross-links between collagen molecules, can lead to multiple age-related disease states such as hypertension with concomitant kidney and neurological defects – such cross-linking may contribute to the accelerated ageing seen in patients with diabetes [25]. The field of mechanobiology and its intersection with ageing is thus very promising in terms of ‘rejuvenation’.

Inflammation: Inflammageing, age-dependent chronic inflammation, is implicated in a wide range of age-related diseases [26]. Ageing correlates with high, levels of inflammatory mediators in the blood, such as IL-1, IL-6, C-reactive protein, IFNα, and several others [27]. Originally inflammation was considered part of the hallmark 'altered intercellular communication', however it could be considered on its own merit, due to its large contribution to the ageing process and its cross-play with other hallmarks such as cellular senescence and the newly proposed gut microbiota [26, 28].

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Eam Taekyoung : Due to a sedentary life, 'gradual change in posture' and/or 'continuous tension in some muscles' can lead to deterioration of autophagy, neurodegeneration, immune aging, deterioration of cell motility, deterioration of cell-to-cell communication function, and It appears to cause stiffness and loss of elasticity. 'Progressive deformation of body posture' causes blood vessels, neural tubes, and lymphatic vessels to gradually atrophy or dents. 'Habitatization of prolonged tension in some muscles' can gradually reduce cell metabolism. Here, these "gradual" changes are aging.

These seem particularly timely, but there will likely be a continuing, ongoing discussion of the ageing hallmarks. In the view of the panel, the framing in terms of hallmarks offers a useful simplification of a very diverse field, especially for newcomers, but it should not be accepted as a sufficient platform for research on the root causes of the ageing process. Nonetheless, the hallmarks have proven useful in identifying targets for intervention in age-related diseases, e.g. therapies targeting the accumulation of senescent cells, with promising results in preclinical models [4–6] and early stage human clinical trials [7].

Furthermore, the panel discussed that the hallmarks of ageing have greater value when viewed as a network rather than individual processes, and more focus on the interconnectedness of different hallmarks is urgently needed, together with wider adoption of systems biology approaches. Recognition that the ageing process results in progressive loss of homeostasis will also be informative for research aiming to restore a youth-like balance, by for example restoring youthful gene/protein expression levels and patterns and/or judicious supplementation of metabolites that have become depleted with age.

When discussing the future of ageing research, it was highlighted that the field as a whole has not yet fully delivered. The ageing process is multifaceted and multifactorial, and the panellists stressed that the classical approach of focussing on single pathways or even individual hallmarks might fail to capture the complexity an interconnectedness of ageing. Furthermore, translational work to in humans should have a stronger focus, especially to evaluate the safety profile of possible interventions (dose, concentration, intervals, etc.).

Eam Taekyung: It seems necessary to reinterpret not only aging but also all chronic diseases from a network perspective.

The work presented in this symposium consisted of some of the latest findings in the field in the context of reevaluated hallmarks of ageing. Here we group and summarize the presentations by overall theme.

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Theories of ageing and cellular senescence

Professor Thomas Kirkwood (University of Newcastle) began his talk examining evolutionary theories of ageing. The theory of the disposable soma [29] describes that an organism has limited resources, which it has to allocate strategically. For instance, allocating resources towards growth may lead to less investment in DNA repair. Secondly, he highlighted the antagonistic pleiotropy hypothesis [30], which outlines that genes leading to harmful effects in old age might not be selected against due to an advantage in early life. Both of these theories derive from the principle that the force of natural selection declines with increasing age (Figure 2).

Eam Taekyung: What genes essentially pursue is survival and reproduction. Although epigenetic characteristics are known to be evolutionarily reflected, "good characteristics to strengthen the viability of humans past the breeding season" are difficult to reflect in the breeding process of the next generation.

Figure 2

The force of natural selection in ageing. The force that selects different traits declines as a function of age after reproductive age. Natural selection benefits survival to maturity and reproduction. Therefore, traits that present harmful effects late in life (selection shadow) will likely have already been passed to the next generation. The figure was generated based on the reference [34].

From here Professor Kirkwood focused on the hallmark of cellular senescence. Together with Dr. Axel Kowald, they analyzed existing data on the use of senolytics in mice using the Gompertz model [31]. While the median lifespan increased by a striking 27%, the maximum lifespan saw marginal increase (2.8%). However, the rate of ageing seems to accelerate with senolytic treatment. This is compatible with the hypothesis that senescent cells can have beneficial effects, such as wound healing, proposed several years ago [32]. This gives further reason for the evolution of senescence-associated secretory phenotype (SASP).

Eam Taekyoung: The fact that the increase in median lifespan is insignificant compared to the increase in maximum lifespan of senolytic drugs may mean that there is a balloon effect that pops out there when you press here. It seems to be proof that we still have a long way to go before we can fully understand aging.

Through modelling studies, Kirkwood and Kowald proposed that while senolytics may cause a short-term improvement in survivorship, they may impair the capacity of the organism to repair itself, which might lead to a faster accumulation of senescent cells when the treatment concludes. This highlights the importance of further analysis to fully understand the potential benefits and side effects of senolytic therapy.

While the importance of cellular senescence in ageing is well established [33], how this process is interconnected to other hallmarks of ageing remains elusive. In her presentation, Professor Lynne Cox (University of Oxford), explored these relationships, emphasising the importance of cellular senescence and deregulated nutrient sensing. She and others found that the inhibition of mTOR, a central regulator of metabolism and growth, leads to an improvement in senescent phenotypes and a delay in cellular senescence [18]. Similarly, mTOR inhibition alleviated the hallmark of mitochondrial dysfunction, with improved mitophagy and reduced mitochondrial load [18]. Senescence-associated changes in the cytoskeleton - proposed as a component of new hallmarks of ageing ‘altered mechanical properties’ (Figure 1) – are intrinsically linked with altered cell-cell communication, with an increase in cell contacts and a higher transfer of mitochondria through tunnelling nanotubes occurring between cells during cellular ageing. Both phenotypes were ameliorated after mTOR inhibition [35]. Finally, mTOR inhibition also alleviated markers of genomic instability and telomere attrition in senescent cells, demonstrating the value of mTOR inhibitors as geroprotectors, consistent with numerous findings from preclinical model organisms [36]; new studies in dogs (DogAgeing Project) and Humans (PEARL Trial) will therefore be particularly informative.

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New insights into telomeres and cellular senescence

Telomere attrition is a central feature of cellular senescence. Still, the effects of stress on telomeres and subsequent premature senescence remain unclear. One proposed model is that oxidative stress induces premature senescence through the shortening of telomeres. To investigate this question, Professor Patricia Opresko (University of Pittsburgh) presented a new cellular tool to precisely induce oxidative stress in the form of 8-oxoguanine in telomeres [37]. Indeed, chronic oxidative stress in immortalized cell lines leads to shortening of telomeres, impaired growth, and genomic instability, while acute stress showed little effect [37].

Eam Taekyung: Why does chronic oxidative stress in immortal cell lines cause telomere shortening, growth disorders and genomic instability, while acute stress shows little effect? Our body has a well-established mechanism for responding to high-intensity short-term stress to respond well to attacks from life-threatening animals. However, this seems to be because there are few mechanisms for responding to low-intensity continuous stress. This is because modern people still have an evolved body suitable for the environment frequently exposed to the threat of predators that could determine life and death in the Paleolithic era.

However, this effect was drastically different in non-disease cells. New data from Opresko’s lab shows that a single dose of oxidative stress at telomeres was enough to inhibit cell growth and induce premature senescence. However, this p53-dependent form of premature senescence was importantly not accompanied by a shortening of telomeres, but rather by telomere fragility. The telomeres were furthermore hypersensitive to replication stress caused by 8-oxoguanine, and it was hypothesized that stalling of replication could explain the arrest in cell growth and premature senescence [38].

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Inflammation, NAD+ and ageing

Cellular senescence, associated with the pro-inflammatory SASP, interlinks with inflammation, which is emerging as an important driver of organismal ageing [39]. Dr. Helena Borland (University of Copenhagen) showed in her short-talk how the compound Urolithin A modulates the cGAS-STING pathway by increasing STING expression, thus amplifying innate immune activation by stimulation. Urolithin A has been reported to possess anti-inflammatory properties for example by reducing activation of another regulator of innate and adaptive immunity, NF-κB [40]. The presented data thus shows that the effects of Urolithin A is context dependent, which is relevant in modulation of the immune response and inflammation.

Professor Eric Verdin (Buck Institute for Research on Ageing) presented new findings regarding CD38, one of several NAD+ consuming enzymes, that is highly expressed on immune cells. NAD+ has become the focus of intense interventional studies over the last decades, since it decreases in several tissues with age and in age-related diseases [41], while supplementation with NAD+ precursors has shown potential to prevent or slow the progression of various age-related diseases, for which there are several on-going clinical trials [42].

Professor Verdin showed that, while NAD+ levels fall, the expression of CD38 in tissue-resident macrophages increases during ageing. NAD+ consuming enzymes stand in competition with each other, and the subsequently higher demand for NAD+ due to overexpressed CD38 might inhibit other NAD+ consuming enzymes critical for geroprotection. Indeed, knock-out of CD38 fully rescued the age-dependent decrease in NAD+ levels in adipose tissue [43]. Taking a closer look at the expression pattern of CD38 the Verdin lab found that there is an age-related increase in the expression of CD38, specifically in resident pro-inflammatory M1 macrophages, supporting the role of inflammation during ageing (Figure 1). The expression of CD38 in macrophages furthermore increased in response to pathogen-associated molecular patterns, but not to damage-associated molecular patterns.

Connecting back to senescence, Professor Verdin's group found that the inflammatory SASP increased CD38 expression in mouse embryonic fibroblasts. In addition, SASP cytokines IL-6, TNF-α, and IL-10 were also capable of inducing CD38 expression. Taken together, CD38 emerges as a novel target to ameliorate age-related diseases, by counteracting inflammation and bringing the dysregulated NAD+ system back to balance.

Among the protective enzymes that compete with CD38 for available NAD+ are the family of poly ADP-ribose polymerases (PARPs). Professor Vilhelm A. Bohr (National Institute on Ageing) presented new data on the DNA damage response enzyme PARP1 related pathways. While the role of PARP1 in nuclear DNA repair and maintenance is well established, a possible role in mitochondria is controversial. Professor Bohr suggested that PARP1 might be present and functional in mitochondria, at least in small amounts.

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Mitochondrial dysfunction

Mitochondrial dysfunction is a central node in the network of hallmarks of ageing and is known to be a strong driver of stem cell ageing [44–46]. Age-related changes in hematopoietic stem cells (HSCs), that are responsible for life-long production of all blood lineages as well as stem cell pool maintenance, cause predisposition to myeloid malignancies, adaptive immune compromise and anaemia. Functional restoration of ageing tissue-resident stem cells is therefore of high interest. Dr. Els Mansell (Lund University and University College London) showed that mitochondrial membrane potential (ΔΨm) decreases in aged hematopoietic stem cells (HSC) but that a small fraction of ΔΨm high HSCs remain present in the bone marrow of old mice. Strikingly, her data reveal that ΔΨm is a stronger determinant of the transcriptional state of HSCs than chronological age. In addition, enhancement of ΔΨm through mitoquinol treatment resulted in rescue of metabolic, transcriptional and functional parameters of old HSC. Importantly, mitochondrial treatment of old mice corrected the age-related myeloid bias in the peripheral blood and improved the engraftment potential of old HSCs [47].

A major cellular process to maintain the quality of mitochondria is mitophagy; ageing and genetic factors that retard mitophagy could lead to accumulation of damaged mitochondria in cells and tissues, a major cause/risk factor of different diseases, including neurodegenerative diseases [48–50]. The importance of dysfunctional mitochondria in age-related diseases was underpinned by Dr. Shuqin Cao (Akershus University Hospital and University of Oslo), who presented data on a novel inducer of mitophagy extracted from Passiflora edulis (passion fruit) ameliorating phenotypes of Alzheimer’s disease in C. elegans and cell models [51]. Furthermore, Dr. Jianying Zhang (University of Oslo and Central South University) showed that the levels of a key autophagy regulator in human cerebrospinal fluid can be used as a potential biomarker to predict the clinical severity and cognitive trajectories in Alzheimer’s disease.

Eam Taekyung: Mitochondria eventually play a role in converting cells into usable energy. The fact that dementia treatment through mitochondrial transplantation is drawing attention as a new treatment for dementia and that aerobic exercise and mitochondrial volume are proportional seems to enable a new interpretation of the cause and countermeasures of dementia. It seems worth noting that the causes and solutions of dementia can be interpreted as follows.  

Dementia is a degenerative disease. Compared to the life expectancy that suddenly began to increase after the 1950s, the physical activity of running or walking decreased due to the influence of the industrial revolution. As a result, human society has rapidly progressed into a sedentary-oriented activity society. In addition, in general, people tend to have a sharp drop in muscle mass after the age of about 40, resulting in a generalized and intensified bent posture in which the head protrudes forward, especially after the age of about 50. As a result, the vascular system passing through the neck area is likely to be pressed or placed in a continuous rigid state. This leads to quantitative and qualitative deterioration of the blood supplied to the brain. It is a degenerative disease.

In order to prevent dementia, it is most important to prevent the neck from bending forward in the average posture in daily life. Next, it is important to reduce the activity of the brain continuously focusing on something because fatigue substances accumulate when breathing less than the energy used. The reason why the life of writing jobs, which are bound to be stressful, is short compared to those with other jobs is also because of breathing.

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Premature ageing and DNA repair

Professor Bohr presented the short-term use of NAD+ supplementation in another age-related pathology, namely presbycusis, or age-related hearing loss. His group has previously shown that supplementation with the NAD+ precursor nicotinamide riboside (NR) partially prevents hearing loss and improves cochlear health in mouse models of Cockayne syndrome (CS), an accelerated ageing disease [52]. However, whether this was translatable to age-related hearing loss in non-disease models was previously unknown. Here, Professor Bohr’s group showed that the treatment of mice with NR was capable of restoring NAD+ in the cochlea of aged mice to the levels found in young mice. Even more strikingly, NR treatment limited the progression of hearing loss in ageing mice while stopping the progression of hearing loss in old mice. Based on distortion product otoacoustic emissions and wave-form analysis, the group hypothesize that the benefit may arise due to an improvement in the inner hair cells, auditory nerves and/or synaptic transmission.

Another characteristic of CS is dysfunctionality in a sub-pathway of nucleotide excision repair (NER), specifically transcription-coupled repair. Professor Jean-Marc Egly (Institut de Génétique et de Biologie Moléculaire et Cellulaire) discussed that CS complementation group A and B (CSA/CSB), the disease-defining proteins in CS, may target Pol II when at a DNA lesion to recruit the NER machinery for repair. However, upon UV stress, cells from CS patients stall in transcription without subsequent recovery. Professor Egly’s group found that this stall of transcription was sustained by the incapability of mutant CSA and CSB to promote degradation of the chromatin-bound protein ATF3 [53], which suppresses thousands of genes as a UV stress response. On the contrary, in wild-type cells, ATF3 has cleared from chromatin 24h post UV treatment. In addition, Professor Egly also presented data on the role of CSA and CSB in the regulation of cell division [54]. CSA and CSB seem to be recruited to the midbody of the cell, recruit ubiquitin ligases CUL4 and MDM2, and promote the degradation of PRC1 to assist cell division. These findings do not only show a potential target for therapy, but may also be useful as a potentially simple clinical marker for CS diagnosis.

An additional premature ageing disease is the genome instability disorder, ataxia-telangiectasia (A-T). A-T is caused by null mutations in the ATM gene, which encodes the homeostatic, multi-functional protein kinase, ATM. A major function of ATM is orchestrating the cellular response to double-strand breaks in the DNA, but it is also involved in regulating the cellular redox balance, mitochondrial homeostasis and several other metabolic circuits. The premature ageing component of A-T is studied by Professor Yosef Shiloh (Tel Aviv University). His work is currently focused on the premature senescence that is a phenotypic hallmark of cultured primary fibroblasts from A-T patients. In view of ATM’s role in the cellular response to reactive oxygen species, this phenotype was examined in cells grown under physiological oxygen level (3%) instead of ambient level (21%). However, the difference in senescence pace between A-T and non-disease cells was maintained. Furthermore, transcriptomic analysis showed strikingly similar dynamics of gene expression patterns in A-T fibroblasts senescing at early passage levels and non-disease cells senescing much later. This observation suggests that the same replicative senescence occurs in both genotypes, but this process is inherently accelerated in A-T cells, highlighting the role of genome stability in determining senescence pace, with implications on organismal ageing.

A-T is an autosomal recessive disease but the phenotypic effects of heterozygosity for A-T mutations has been a focus of interest and some controversies for many years, particularly with regard to cancer predisposition conferred by this genotype. To this end, Professor Yosef Shiloh presented data from an ongoing epidemiological study, in which a large Israeli cohort of A-T carriers and controls has been followed since the late 1990s. As these individuals are advancing in age, a moderate but significant increase of cancer occurrence is being observed among the carriers compared to controls suggesting mild predisposition to many types of cancers among the carriers. Initial findings also suggest a moderate increase in cardiovascular diseases to be associated with this genotype. Since A-T carrier frequency may reach 1% – 3% in various populations these findings highlight the role of genome stability in common human morbidity. Collectively, sequence alterations in many genes associated with maintenance of genome integrity may implicate significantly of ageing and ageing-associated morbidity in the general population.

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Cardiovascular, cerebrovascular and muscular pathologies of ageing

Most of the preclinical experimental studies on the mechanism of endothelial dysfunction are experimentally separated from vascular ageing, even though the latter represents the major driver of deterioration of endothelial function, vascular stiffness and of cardiovascular diseases in humans. In this context, Professor Stefan Chlopicki (Jagiellonian University) highlighted the importance of the accelerated age-dependent development of endothelial dysfunction in the pathogenesis of cardiovascular disease based on experimental studies performed with the use of the unique MRI-based in vivo methodology to characterize endothelial function in murine models of dyslipidaemia and vascular ageing [55, 56].

The cerebrovascular function also declines with age. Especially the cerebrovascular reactivity to vasodilating stimuli and the perfusion modulation is affected [57], with severe decline being observed in diverse neurodegenerative diseases. Dr. Mark Vestergaard (Rigshospitalet) showed that a correlation between subtle cognitive deficits and an inhibited cerebrovascular response to neuronal activation can be observed before the rise of neurodegeneration [58].

Currently, lifestyle factors like diet and exercise are still the best protectors against age-related diseases. On this note, Dr. Casper Soendenbroe provided novel evidence that even physical activity performed at a recreational level offers some protection against the debilitating effects of ageing [59]. Specifically, lifelong exercising men had preserved levels of muscle stem cells and improved neuromuscular innervation, which culminated in a clinically relevant preservation of muscle function.

Eam Taekyung: I believe that almost all chronic disease are likely to occur with the following mechanisms. It is also important to note that posture, breathing, and psychological stress need to be viewed from a network perspective, and to shift the big trend of medical research.

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Concluding remarks

The symposium hosted several established researchers and young scientists in the field to present and discuss the latest findings in age-related research, and how this work connects to established and newly proposed hallmarks of ageing. The symposium was held as a hybrid event, with both physical and virtual attendance. The large international audience that was amassed highlights the growing interest in the field.

The presented data showcased novel research at the forefront of the field, with a focus on a possible increase in healthspan and the amelioration of age-related diseases. Here, both the possible clearance or delay of senescent cells as well as possible interventions in the NAD+ system were discussed. While both of these approaches are promising, they are not without limitations.

At this point, tremendous progress has occurred, but a unified theory of ageing that can fully explain the process is still missing, and many open questions remain, both on a cellular and organismal level. Whether it is possible to target the ageing process at its core, or whether a combination of approaches is needed to target the aspects encompassing ageing, remains to be solved in the future.

Eam Taekyung: If you would like to know more about the relationship between posture and disease, please refer to the link below.

The 8 main principles of body posture

The 3 main principles of breathing posture

The 6 main principles of mind posture

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ACKNOWLEDGMENTS

We thank Novo Nordisk Foundation for financial and catering supports. Partial materials used to generate Figure 1 were from BioRender subscribed by the Fang laboratory.

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Footnotes