Browsed by
Tag: reason

UNITY Biotechnology Raises $116M for Senescent Cell Clearance Development – Article by Reason

UNITY Biotechnology Raises $116M for Senescent Cell Clearance Development – Article by Reason

Comments 1 comment
The New Renaissance HatReason
******************************

The whispers of late have had it that UNITY Biotechnology was out raising a large round of venture funding, and their latest press release shows that this was indeed the case. The company, as you might recall, is arguably the more mainstream of the current batch of startups targeting the clearance of senescent cells as a rejuvenation therapy. The others include Oisin Biotechnologies, SIWA Therapeutics, and Everon Biosciences, all with different technical approaches to the challenge. UNITY Biotechnology is characterized by a set of high profile relationships with noted laboratories, venture groups, and big names in the field, and, based on the deals they are doing, appear to be focused on building a fairly standard drug development pipeline: repurposing of apoptosis-inducing drug candidates from the cancer research community to clear senescent cells, something that is being demonstrated with various drug classes by a range of research groups of late. Senescent cells are primed to apoptosis, so a nudge in that direction provided to all cells in the body will have little to no effect on normal cells, but tip a fair proportion of senescent cells into self-destruction. Thus the UNITY Biotechnology principals might be said to be following the standard playbook to build the profile of a hot new drug company chasing a hot new opportunity, and clearly they are doing it fairly well so far.

UNITY Biotechnology Announces $116 Million Series B Financing

Quote:

UNITY Biotechnology, Inc. (“UNITY”), a privately held biotechnology company creating therapeutics that prevent, halt, or reverse numerous diseases of aging, today announced the closing of a $116 million Series B financing. The UNITY Series B financing ranks among the largest private financings in biotech history and features new investments from longtime life science investors ARCH Venture Partners, Baillie Gifford, Fidelity Management and Research Company, Partner Fund Management, and Venrock. Other investors include Bezos Expeditions (the investment vehicle of Jeff Bezos) and existing investors WuXi PharmaTech and Mayo Clinic Ventures. Proceeds from this financing will be used to expand ongoing research programs in cellular senescence and advance the first preclinical programs into human trials.

The financing announcement follows the publication of research that further demonstrates the central role of senescent cells in disease. The paper, written by UNITY co-founders Judith Campisi and Jan van Deursen and published today, describes the central role of senescent cells in atherosclerotic disease and demonstrates that the selective elimination of senescent cells holds the promise of treating atherosclerosis in humans. In animal models of both early and late disease, the authors show that selective elimination of senescent cells inhibits the growth of atherosclerotic plaque, reduces inflammation, and alters the structural characteristics of plaque such that higher-risk “unstable” lesions take on the structural features of lower-risk “stable” lesions. “This newly published work adds to the growing body of evidence supporting the role of cellular senescence in aging and demonstrates that the selective elimination of senescent cells is a promising therapeutic paradigm to treat diseases of aging and extend healthspan. We believe that we have line of sight to slow, halt, or even reverse numerous diseases of aging, and we look forward to starting clinical trials with our first drug candidates in the near future.”

So this, I think, bodes very well for the next few years of rejuvenation research. It indicates that at least some of the biotechnology venture community understands the likely true size of the market for rejuvenation therapies, meaning every human being much over the age of 30. It also demonstrates that there is a lot of for-profit money out there for people with credible paths to therapies to treat the causes of aging. It remains frustrating, of course, that it is very challenging to raise sufficient non-profit funds to push existing research in progress to the point at which companies can launch. This is a problem throughout the medical research and development community, but it is especially pronrounced when it comes to aging. The SENS view of damage repair, which has long incorporated senescent cell clearance, is an even tinier and harder sell within the aging research portfolio – but one has to hope that funding events like this will go some way to turn that around.

From the perspective of being an investor in Oisin Biotechnologies, I have to say that this large and very visible flag planted out there by the UNITY team is very welcome. The Oisin team should be able to write their own ticket for their next round of fundraising, given that the gene therapy technology they are working on has every appearance of being a superior option in comparison to the use of apoptosis-inducing drugs: more powerful, more configurable, and more adaptable. When you are competing in a new marketplace, there is no such thing as too much validation. The existence of well-regarded, well-funded competitors is just about the best sort of validation possible. Well-funded competitors who put out peer-reviewed studies on a regular basis to show that the high-level approach you and they are both taking works really well is just icing on the cake. Everyone should have it so easy. So let the games commence! Competition always drives faster progress. Whether or not I had skin in this game, it would still be exciting news. The development of rejuvenation therapies is a game in which we all win together, when new treatments come to the clinic, or we all lose together, because that doesn’t happen fast enough. We can and should all of us be cheering on all of the competitors in this race. The quality and availability of the outcome is all that really matters in the long term. Money comes and goes, but life and health is something to be taken much more seriously.

Now with all of that said, one interesting item to ponder in connection to this round of funding for UNITY is the degree to which it reflects the prospects for cancer therapies rather than the prospects for rejuvenation in the eyes of the funding organizations. In other words, am I being overly optimistic in reading this as a greater understanding of the potential for rejuvenation research in the eyes of the venture community? It might be the case that the portions of the venture community involved here understand the market for working cancer drugs pretty well, and consider that worth investing in, with the possibility of human rejuvenation as an added bonus, but not one that is valued appropriately in their minds. Consider that UNITY Biotechnology has partnered with a noted cancer therapeutics company, and that the use of drugs to inducing apoptosis is a fairly well established approach to building cancer treatments. That is in fact why there even exists a range of apoptosis-inducing drugs and drug candidates for those interested in building senescent cell clearance therapies to pick through. Further, the presence of large numbers of senescent cells does in fact drive cancer, and modulating their effects (or removing them) to temper cancer progress is a topic under exploration in the cancer research community. So a wager on a new vision, or a wager on the present market? It is something to think about.

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries.
***
This work is reproduced here in accord with a Creative Commons Attribution license. It was originally published on FightAging.org.
An Example of the Glaring Lack of Ambition in Aging Research – Post by Reason

An Example of the Glaring Lack of Ambition in Aging Research – Post by Reason

Comments 0 Comment
The New Renaissance HatReason
******************************

The mainstream of aging research, at least in public, is characterized by a profound lack of ambition when it comes to treating aging as a medical condition. Researchers talk about slightly altering the trajectory of aging as though that is the absolute most that is possible, the summit of the mountain, and are in many cases ambivalent when it comes to advocating for even that minimal goal. It is this state of affairs that drove Aubrey de Grey and others into taking up advocacy and research, given that there are clear paths ahead to rejuvenation, not just a slight slowing of aging, but halting and reversing the causes of aging. Arguably embracing rejuvenation research programs would in addition cost less and take a much shorter span of time to produce results, since these programs are far more comprehensively mapped out than are efforts to produce drugs to alter the complex operations of metabolism so as to slightly slow the pace at which aging progresses. It is most frustrating to live in a world in which this possibility exists, yet is still a minority concern in the research community. This article is an example of the problem, in which an eminent researcher in the field takes a look at a few recently published books on aging research, and along the way reveals much about his own views on aging as an aspect of the human condition that needs little in the way of a solution. It is a terrible thing that people of this ilk are running the institutes and the funding bodies: this is a field crying out for disruption and revolution in the name of faster progress towards an end to aging.

Quote from “Want to Live Longer? Our Complicated Relationship to Longevity” by Tom Kirkwood:

How can we overcome our niggling suspicion that there is something dubious, if not outright wrong, about wanting to live longer, healthier lives? And how might we pursue longer lives without at the same time falling prey to quasiscientific hype announcing imminent breakthroughs? In order to understand why aging is changing, and what this means for our futures, we need to learn more about the aging process itself. As a biologist who specializes in aging, I have spent more than four decades on a quest to do exactly this. Not only have I asked why aging should occur at all (my answer is encapsulated in a concept called disposability theory), but I have also sought to understand the fastest-growing segment of the population – those aged 85 and above. The challenges inherent in understanding and tackling the many dimensions of aging are reflected in a clutch of new books on the topic. Are these books worth reading? Yes and no. They take on questions like: Can we expect increases in human longevity to continue? Can we speed them up? And, on the personal level, what can we do to make our own lives longer and healthier? If nothing else, these books and their varied approaches reveal how little we actually know.

To find out more about factors that can influence our individual health trajectories across ever-lengthening lives, my colleagues and I began, in 2006, the remarkable adventure of the still ongoing Newcastle 85+ Study, an extremely detailed investigation of the complex medical, biological, and social factors that can affect a person’s journey into the outer reaches of longevity. For each individual, we determined whether they had any of 18 age-related conditions (e.g., arthritis, heart disease, and so on). Sadly, not one of our 85-year-olds was free of such illnesses. Indeed, three quarters of them had four or more diseases simultaneously. Yet, when asked to self-rate their health, an astonishing 78 percent – nearly four out of five – responded “good,” “very good,” or “excellent.” This was not what we had expected. The fact that these individuals had so many age-related illnesses fit, of course, with the popular perception of the very old as sadly compromised. But the corollary to this perception – that in advanced old age life becomes a burden, both to the individuals themselves and to others – was completely overturned. Here were hundreds of old people, of all social classes and backgrounds, enjoying life to the fullest, and apparently not oppressed by their many ailments.

As for my stake in the enterprise, I began investigating aging when I was in my early 20s – well before I had any sense of my own body aging. Quite simply, I was curious. What is this mysterious process, and why does it occur? Everything else in biology seems to be about making things work as well as they can, so how is it that aging destroys us? Now that I am growing older myself, my research helps me understand my own body and reinforces the drive to live healthily – to eat lightly and take exercise – though not at the cost of eliminating life’s pleasures. For all that I have learned about aging, my curiosity remains unabated. Indeed, it has grown stronger, partly because as science discovers more about the process, it reveals that there is ever more to learn, ever greater complexity to unravel, and partly because I am now my own subject: through new physical and psychological experiences in myself, I learn more about what older age is really like. I know all too well that the next phase of my life will bring unwelcome changes, and of course it must end badly. But the participants of the Newcastle 85+ Study have shown me that the journey will not be without interest.

Link: https://lareviewofbooks.org/article/want-live-longer-complicated-relationship-longevity/

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries.
***
This work is reproduced here in accord with a Creative Commons Attribution license. It was originally published on FightAging.org.
Criticizing Programmed Theories of Aging – Article by Reason

Criticizing Programmed Theories of Aging – Article by Reason

Comments 1 comment
The New Renaissance HatReason
******************************

Today I’ll point out an open-access critique of programmed aging theories by the originator of the disposable soma theory of aging, one of the modern views of aging as accumulated damage rather than programming. The question of how and why we age is wrapped in a lot of competing theory, but of great practical importance. Our biochemistry is enormously complex and incompletely mapped, and thus the processes of aging, which is to how exactly our biochemistry changes over time, and all of the relationships that drive that change, are also enormously complex and incompletely mapped. Nonetheless, there are shortcuts that can be taken in the face of ignorance: the fundamental differences between young and old tissue are in fact well cataloged, and thus we can attempt to reverse aging by treating these changes as damage and repairing them. If you’ve read through the SENS rejuvenation research proposals, well, that is the list. The research community may not yet be able to explain and model how exactly this damage progresses, interacts, and spreads from moment to moment, but that effort isn’t necessary to build repair therapies capable of rejuvenation. You don’t need to build a full model of the way in which paint cracks and peels in order to scrub down and repaint a wall, and building that model is a lot most costly than just forging ahead with the painting equipment.

The engineering point of view described above, simply getting on with the job when there is a good expectation of success, is somewhat antithetical to the ethos and culture of the sciences, which instead guides researchers to the primary goal of obtaining full understanding of the systems they study. In practice, of course, every practical application of the life sciences is created in a state of partial ignorance, but the majority of research groups are nonetheless oriented towards improving the grand map of the biochemistry of metabolism and aging rather than doing what can be done today to create rejuvenation therapies. Knowledge over action. If we had all the time in the world this would be a fine and golden ideal. Unfortunately we do not, which places somewhat more weight on making material progress towards the effective treatment of aging as a medical condition – ideally by repairing its causes.

But what are the causes of aging? The majority view in the research community is that aging is a process of damage accumulation. The normal operation of metabolism produces forms of molecular damage in cells and tissues, a sort of biological wear and tear – though of course the concept of wear and tear is somewhat more nuanced and complex in a self-repairing system. This damage includes such things as resilient cross-links that alter the structural properties of the extracellular matrix and toxic metabolic waste that clutters and harms long-lived cells. As damage accumulates, our cells respond in ways that are a mix of helpful and harmful, secondary and later changes that grow into a long chain of consequences and a dysfunctional metabolism that is a long way removed from the well-cataloged fundamental differences between old and young tissues. An old body is a complicated mess of interacting downstream problems. In recent years, however, a growing minority have suggested and theorized that aging is not caused by damage, but is rather a programmed phenomenon – that some portion of the what I just described as the chain of consequences, in particular epigenetic changes, are in fact the root cause of aging. In the programmed view of aging, epigenetic change causes dysfunction and damage, not the other way around. That these two entirely opposite views can exist is only possible because there is no good map of the detailed progression of aging – only disconnected snapshots and puzzle pieces. There is a lot of room to arrange the pieces in any way that can’t be immediately refuted on the basis of well-known past studies.

There are two ways to settle the debate of aging as damage versus aging as evolved program. The first is to produce that grand map of metabolism and aging, something that I suspect is at the least decades and major advances in life science automation removed from where we stand now. The other is to build therapies that produce large degrees of rejuvenation, enough of a difference to put it far beyond argument that the approach taken is the right one. That is not so far away, I believe, as the first SENS rejuvenation therapies are presently in the early stages of commercial development. I think that, even with the comparative lack of funding for this line of development, ten to twenty years from now the question will be settled beyond reasonable doubt. Meanwhile, the programmed-aging faction has become large enough and their positions coherent enough that the mainstream is beginning to respond substantially to their positions; I expect that this sort of debate will continue all the way up to and well past the advent of the first meaningful rejuvenation therapies, which at this point look to be some form of senescent cell clearance.

Can aging be programmed? A critical literature review – by Axel Kowald and Thomas B. L. Kirkwood

Quote:

Many people, coming new to the question of why and how aging occurs, are attracted naturally to the idea of a genetic programme. Aging is necessary, it is suggested, either as a means to prevent overcrowding of the species’ environment or to promote evolutionary change by accelerating the turnover of generations. Instead of programmed aging, however, the explanation for why aging occurs is thought to be found among three ideas all based on the principle that within iteroparous species (those that reproduce repeatedly, as opposed to semelparous species, where reproduction occurs in a single bout soon followed by death), the force of natural selection declines throughout the adult lifespan. This decline occurs because at progressively older ages, the fraction of the total expected reproductive output that remains in future, on which selection can act to discriminate between fitter and less-fit genotypes, becomes progressively smaller. Natural selection generally favours the elimination of deleterious genes, but if its force is weakened by age, and because fresh mutations are continuously generated, a mutation-selection balance results. The antagonistic pleiotropy theory suggests that a gene that has a benefit early in life, but is detrimental at later stages of the lifespan, can overall have a net positive effect and will be actively selected. The disposable soma theory is concerned with optimizing the allocation of resources between maintenance on the one hand and other processes such as growth and reproduction on the other hand. An organism that invests a larger fraction of its energy budget in preventing accumulation of damage to its proteins, cells and organs will have a slower rate of aging, but it will also have fewer resources available for growth and reproduction, and vice versa. Mathematical models of this concept show that the optimal investment in maintenance (which maximizes fitness) is always below the fraction that is necessary to prevent aging.

In recent years, there have been a number of publications claiming that the aging process is a genetically programmed trait that has some form of benefit in its own right. If this view were correct, it would be possible experimentally to identify the responsible genes and inhibit or block their action. This idea is, however, diametrically opposed to the mainstream view that aging has no benefit by its own and is therefore not genetically programmed. Because experimental strategies to understand and manipulate the aging process are strongly influenced by which of the two opinions is correct, we have undertaken here a comprehensive analysis of the specific proposals of programmed aging. On the principle that any challenge to the current orthodoxy should be taken seriously, our intention has been to see just how far the various hypotheses could go in building a convincing case for programmed aging.

This debate is not only of theoretical interest but has practical implications for the types of experiments that are performed to examine the mechanistic basis of aging. If there is a genetic programme for aging, there would be genes with the specific function to impair the functioning of the organism, that is to make it old. Under those circumstances, experiments could be designed to identify and inhibit these genes, and hence to modify or even abolish the aging process. However, if aging is nonprogrammed, the situation would be different; the search for genes that actively cause aging would be a waste of effort and it would be too easy to misinterpret the changes in gene expression that occur with aging as primary drivers of the senescent phenotype rather than secondary responses (e.g. responses to molecular and cellular defects). It is evident, of course, that genes influence longevity, but the nature of the relevant genes will be very different according to whether aging is itself programmed or not.

For various programmed theories of aging, we re-implemented computational models, developed new computational models, and analysed mathematical equations. The results fall into three classes. Either the ideas did not work because they are mathematically or conceptually wrong, or programmed death did evolve in the models but only because it granted individuals the ability to move, or programmed death did evolve because it shortened the generation time and thus accelerated the spread of beneficial mutations. The last case is the most interesting, but it is, nevertheless, flawed. It only works if an unrealistically fast-changing environment or an unrealistically high number of beneficial mutations are assumed. Furthermore and most importantly, it only works for an asexual mode of reproduction. If sexual reproduction is introduced into the models, the idea that programmed aging speeds up the spread of advantageous mutations by shortening the generation time does not work at all. The reason is that sexual reproduction enables the generation of offspring that combine the nonaging genotype of one parent with the beneficial mutation(s) found in the other parent. The presence of such ‘cheater’ offspring does not allow the evolution of agents with programmed aging.

In summary, all of the studied proposals for the evolution of programmed aging are flawed. Indeed, an even stronger objection to the idea that aging is driven by a genetic programme is the empirical fact that among the many thousands of individual animals that have been subjected to mutational screens in the search for genes that confer increased lifespan, none has yet been found that abolishes aging altogether. If such aging genes existed as would be implied by programmed aging, they would be susceptible to inactivation by mutation. This strengthens the case to put the emphasis firmly on the logically valid explanations for the evolution of aging based on the declining force of natural selection with chronological age, as recognized more than 60 years ago. The three nonprogrammed theories that are based on this insight (mutation accumulation, antagonistic pleiotropy, and disposable soma) are not mutually exclusive. There is much yet to be understood about the details of why and how the diverse life histories of extant species have evolved, and there are plenty of theoretical and experimental challenges to be met. As we observed earlier, there is a natural attraction to the idea that aging is programmed, because developmental programming underpins so much else in life. Yet aging truly is different from development, even though developmental factors can influence the trajectory of events that play out during the aging process. To interpret the full complexity of the molecular regulation of aging via the nonprogrammed theories of its evolution may be difficult, but to do it using demonstrably flawed concepts of programmed aging will be impossible.

Given that the author here has in the past been among those who dismissed the SENS initiative as an approach to treating aging by repairing damage, it is perhaps a little amusing to see him putting forward points such as this one: “despite the cogent arguments that aging is not programmed, efforts continue to be made to establish the case for programmed aging, with apparent backing from quantitative models. It is important to take such claims seriously, because challenge to the existing orthodoxy is the path by which science often makes progress.” Where was this version of the fellow ten years ago?

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries.
***
This work is reproduced here in accord with a Creative Commons Attribution license. It was originally published on FightAging.org.
The Rational Argumentator’s Fourteenth Anniversary Manifesto: Who Is the Western Man?

The Rational Argumentator’s Fourteenth Anniversary Manifesto: Who Is the Western Man?

Comments 0 Comment
The New Renaissance Hat
G. Stolyarov II
August 31, 2016
******************************

Who Is the Western Man?

On the fourteenth anniversary of The Rational Argumentator, it is fitting to consider the tagline that has been featured on TRA since its founding: “A Journal for Western Man”. But who is this Western Man for whom The Rational Argumentator is intended? In 2002, the answer to that question seemed rather apparent for at least a substantial segment of then-prevalent libertarian, conservative, and Objectivist thinkers who, each in their own way, understood the Western Man to stand for the general cultural ideals and noblest aspirations of Western civilization.

Unfortunately, the decade of the 2010s and the past two years especially have seen the rise of a noxious and fundamentally anti-Western, anti-modern, and anti-civilization movement known as the “alt-right”, which has attempted to appropriate the rhetoric of Western culture and even of the Renaissance for itself. The Rational Argumentator will not allow this appropriation to remain unchallenged. TRA stands resolutely in opposition to all forms of bigotry, racism, nativism, misogyny, and any other circumstantially rooted intolerance – all of which are contrary to the ideals of high Western civilization. But at the same time, The Rational Argumentator also cannot cave to the “social justice” campus activism of the far Left, which would have even the very identification of Western culture and civilization banished, lest it offend the ever-more-delicate sensibilities of firebrand youths who resolutely refuse to let knowledge of the external world get in the way of their “feelings” and subjective experiences. TRA will not abandon the Western Man, but will continue to explain what it is that the Western Man represents and why these principles are more important and enduring than any tumultuous, ephemeral, and most likely futile and self-defeating activist movements of our era.

So who is the Western Man? It is a not a particular man from the West. It is not a descriptor limited to a particular subset of individuals based on their birth, skin color, national origin, or even gender. Indeed, my original intent behind the “Western Man” descriptor was specifically to salvage the generic term “man” – meaning an archetypical representative of humankind – from any suggestions that it must necessarily be gender-specific. This subtitle was meant transparently to imply, “Of course, ‘Western Man’ includes women, too!”  Some of the greatest and most courageous Western Men – from Hypatia of Alexandria to Mary Wollstonecraft to Ayn Rand to Ayaan Hirsi Ali – have been women.

A Western Man can have been born anywhere, have any physical features, any age, any gender (or lack of gender identity), any sexual preferences (or lack thereof), any religion (or lack thereof) – as long as he/she/it is a thinking being who accepts the valuable contributions of Western culture and civilization and seeks to build upon them. If self-aware, rational artificial intelligences are developed in the future, or if an intelligent alien species comes into contact with us, these beings could potentially be Western Men as well.

A Western Man will respect and seek to learn from the great philosophy, literature, art, music, natural and social sciences, mathematics, and political theory that flourished in Western societies throughout the past three millennia – although by no means is a Western man required to focus exclusively on ideas that originated in the West. Indeed, Western culture itself has unceasingly interacted with and absorbed the intellectual contributions of Egyptian, Mesopotamian, Arabic, Persian, Indian, Chinese, Korean, and Japanese thinkers and creators – to provide just a few examples. Likewise, a great deal of hope for the future of Western civilization can be found among entrepreneurs in Asia, Africa, and Latin America who have endeavored, with notable success, to spread the technologies of the digital age, construct great buildings, and lift billions of people out of abject poverty and into humane and respectable living standards accompanied by ever-increasing longevity.

A Western Man is someone who embraces the ideal of cosmopolitan universalism – a rejection of circumstantially defined tribalism, of the casting of people as “one of us” or “the other” based on attributes that they did not choose. This cosmopolitan universalism is the product of both a long-evolving philosophical framework and the material abundance that enabled the broadening of what Adam Smith termed our circles of sympathy to encompass ever more people.

The edifice of Western philosophical thought has been built upon by thinkers since the times of Thales, Socrates, and Aristotle – but its greatest intellectual breakthroughs were made during the 18th-century Age of Enlightenment. The Western Men who embraced these ideals were often personally flawed; they were men of their time and constrained by the practical realities and social mores that surrounded them. Some Western Men throughout history have, unfortunately, owned slaves, respected individual liberty only in some instances, or been improperly prejudiced against broad groups of people due to ignorance or gaps in the consistent application of their principles. Nonetheless, the legacy of their work – the notions of universal, inalienable individual rights and the preciousness of each person’s liberty and humanity – has been indispensable for later accomplishments, such as the abolition of slavery, women’s suffrage and liberation, civil and privacy rights, cultural and legal acceptance of homosexuality, and recognition of individual rights for members of religious minorities, atheists, and children. If we are able to see farther and know better than to repeat some of the moral errors of the past, it is because, to paraphrase Sir Isaac Newton, we stand on the shoulders of intellectual giants who paved the way for our embrace of the aforementioned great cultural achievements.

The ideals of peaceful commerce and cultural exchange – indeed, cultural appropriation (in an educated, informed, and deliberate manner) of the best elements of every time, place, and way of life – have resulted in a dramatic reduction in warfare, a general decline in nationalistic and tribal hatreds, and a widespread understanding of the essential humanity of our fellows in all parts of the world. Were it not for the intellectual achievements of Western civilization and the global commercial and industrial networks to which it gave rise, humankind would still be embroiled in a bitter, Hobbesian war of all against all. A Western Man is anyone who gives the essential achievements of modernity their well-deserved recognition and admiration, and who studies and offers justified respect to the forebears and authors of these achievements. A Western Man is also anyone who seeks to build upon these accomplishments and add his, her, or its distinctive bricks to the edifice of human progress.

A Western Man is not a fanatic or a bully, and sees fanatics and bullies as the threats to civilization that they are. A Western Man does not use ideology to stifle peaceful expression or compel others to dutifully “know their place” within some would-be totalitarian static social order. A Western Man knows that some people will disagree with him, her, or it, and they have the right to disagree peacefully. However, they do not have the right to be protected from attempts at persuasion or the presentation of diverse and possibly contrary views.

A Western Man embraces reason as the way to discover more about the external world and about human beings. Reason is not the exclusive province of any subset of people; anyone is capable of it, but it takes training and effort – and great respect for the intellect – to utilize consistently and properly. From reason stem the empirical scientific method, the deductive processes of formal logic and mathematics, and the application of empirical and logical truths to the development of technology which improves the human condition. A Western Man does not vilify technology, but rather sees it as a key driver of human progress and an enabler of moral growth by giving people the time and space which prosperity affords, making possible contemplation of better ways of living and relating to others – a prerogative only available to those liberated from hand-to-mouth subsistence.

The ideal of the Western Man is to maintain the great things which have already been brought into this world, and to create new achievements that further improve human life. There is thus both a conservative and a progressive motive within the Western Man, and they must combine to sustain a rich and vital civilization. A Western Man can go by labels such as “liberal”, “conservative”, “libertarian”, “progressive”, or “apolitical” – as long as they are accompanied by careful thought, study, discernment, work ethic, and an earnest desire to build what is good instead of, out of rage or spite, tearing down whatever exists. Conservation of great achievements and progress in creating new achievements are not antagonists, but rather part of the same essential mode of functioning of the Western Man – transcending petty and often false political antagonisms which needlessly create acrimony among people who should all be working to take civilization to the next level.

The next level of civilization – the unceasing expansion of human potential – is the preoccupation of the Western Man. This – not descending into contrived identitarian antagonisms – is the great project of our era. Building on the philosophical groundwork laid by Enlightenment humanism and its derivatives, a Western Man can explore the next stage of intellectual evolution – that of transhumanism, which promises to liberate humankind from its age-old shackles of death, disease, severe scarcity, Earth-boundedness, and internecine conflict.

Who is the Western Man? If you accept the challenge and the honor of supporting and building upon the great civilization which offers us unparalleled opportunities to create a glorious future for all – then the Western Man can be you.

TRA Statistics and Achievements During Its Fourteenth Year

TRA published 211 regular features during its fourteenth year, a rate of publication comparable to that of the eleventh and thirteenth years, while remaining below the extremely active tenth and twelfth years, as shown in the table below:

TRA Year Regular Features Published Page Views in Year
10th 306 1,302,774
11th 208 1,077,192
12th 314 1,430,226
13th 228 892,082
14th 211 823,968

With slightly less content published during the fourteenth year, and a similar average number of page views per published feature (3,905.06 in the fourteenth year versus 3,912.64 in the thirteenth year), it could be expected that total page views would decline slightly. While TRA did not reach the milestone of 10,000,000 cumulative page views during its fourteenth year, it did come the overwhelming majority of the way toward it. Total lifetime TRA visitation currently stands at 9,892,636 page views. However, I am confident that the 10-million page-view threshold will be exceeded within the next two months.

I have reason to expect that publication activity will again accelerate during TRA’s fifteenth year, although this may not occur immediately. Over the past year, I have been occupied with satisfying some of the last remaining requirements of my actuarial studies, and their successful completion is in sight. In the meantime, I collaborated with ACTEX Publications to produce a major 400-page commercial study guide, Practice Problems in Advanced Topics in General Insurance, for SOA Exam GIADV.

Several large-scale endeavors within the transhumanist and life-extensionist movements were pursued over the past year. TRA’s anniversary (August 31) coincides with the date of formation of the Nevada Transhumanist Party, a non-election-oriented, non-donation-accepting, policy-oriented party that advocates for the widespread adoption of emerging technologies, individual liberty, and the pursuit of indefinite life extension. The Nevada Transhumanist Party has grown to 107 members during its first year and has been a forum for numerous thought-provoking discussions. Nevada Transhumanist Party activities have occurred online via its Facebook page and its hosted video panels, such as the Panel Discussion on Hereditary Religion, a conversation among Transhumanist Libertarians and Socialists, and the panel for International Longevity Day, in collaboration with MILE – the Movement for Indefinite Life Extension – entitled “How Can Life Extension Become as Popular as the War on Cancer?” In-person activities of the Nevada Transhumanist Party included attendance at a university political lecture, a local Libertarian candidate’s campaign event, and RAAD Fest, the largest in-person gathering of life-extension supporters to date, where I personally met and spoke with such luminaries of the life-extension movement as Aubrey de Grey, Bill Andrews, and Zoltan Istvan.

Gradual but fundamental shifts are occurring that will contribute to more frequent and impactful activity on The Rational Argumentator’s pages during its fifteenth year. As the overview of the Western Man in this manifesto indicates, the importance of TRA’s work and ideals remains paramount. TRA will remain a bulwark of thoughtful consistency in an era where it seems entire societies have become unmoored from core principles that are integral to a successful civilization. We will steadfastly champion the virtues of reason and deliberation, discussion and civil debate, individualism and classical liberal tolerance, creation and maintenance. Even when the tumult of current events calls into question the foundations of civilized life, TRA will be here to reaffirm and uphold them.

This essay may be freely reproduced using the Creative Commons Attribution Share-Alike International 4.0 License, which requires that credit be given to the author, G. Stolyarov II. Find out about Mr. Stolyarov here.

An Interview with Kelsey Moody of Ichor Therapeutics, Bringing a SENS Therapy for Macular Degeneration to the Clinic – Article by Reason

An Interview with Kelsey Moody of Ichor Therapeutics, Bringing a SENS Therapy for Macular Degeneration to the Clinic – Article by Reason

Comments 0 Comment
The New Renaissance HatReason
******************************

As I mentioned last week, earlier this year Fight Aging! invested a modest amount in the Ichor Therapeutics initiative to develop a treatment for macular degeneration, joining a number of other amateur and professional investors in helping to get this venture started. The approach taken here is based on the results of research carried out at the Methuselah Foundation and SENS Research Foundation over much of the past decade, funded by philanthropists and the support of our community of longevity science enthusiasts. This is how we succeed in building the future: medical science in the laboratory leads to medical development in startup companies, each new stage bringing treatments capable of repairing specific forms of age-related molecular damage that much closer to the clinic.

Ichor Therapeutics is one of a growing number of success stories to emerge from the SENS rejuvenation research community. Young scientists, advocates, and donors involved in earlier projects – years ago now – have gone on to build their own ventures, while retaining an interest in stepping up to do something meaningful to help bring an end to aging. Back in 2010, Kelsey Moody worked on the LysoSENS project to find ways to break down damaging metabolic waste in old tissues; fast-forward six years, and he is the now the CEO of a successful small biotechnology company with a great team, taking that very same technology and putting it to good use. I recently had the chance to ask Kelsey a few questions about the future of SENS rejuvenation research, as well as how the Ichor scientists intend to construct a new class of therapy for macular degeneration, one based on removing one of the root causes of the condition.

Quote:

Who are the people behind Ichor Therapeutics? How did you meet and decide that this was the thing to do? Why macular degeneration as a target?

People have always been the focus of Ichor. Since day one we have worked to create a positive environment that cultivates a product-oriented research focus and emphasizes autonomy and personal accountability for work. As a result, ambitious self-starters tend to find their way to Ichor and remain here. However, we recognized early on that just filling a lab with a bunch of blue-eyed bushy tailed young up-and-comers is not sufficient to develop a robust, mature, translational pipeline. We have augmented our team with a number of critical staff members who are seasoned pharma operators, including our Quality Assurance Director and General Counsel.

Age-related macular degeneration (AMD) was chosen as a target because we believe it is the closest SENS therapy to the clinic. While we obviously have an interest in providing cures for the patients suffering from AMD and are attracted to the large market opportunities such a treatment could bring, our broader interest is in validating the entire SENS paradigm. We believe that Aubrey de Grey continues to receive excessive criticism because nothing spun out of SENS has ever made it into a legitimate pre-clinical pipeline, much less to the bedside. However, this does not mean he is wrong. Our goal is to be the first group to bring a SENS inspired therapy into the clinic and in doing so, silence critics and generate new energy and capital for this cause.

I understand there’s a lengthy origin story for the approach you are taking to treat AMD; it’d be great to hear some of it.

Our approach to treating AMD is based on the hypothesis that cellular junk that accumulates over the lifespan significantly contributes to the onset and progression of AMD. Our goal is to periodically reduce the burden of the junk so it never accumulates to levels sufficient to induce pathology. The strategy to accomplish this calls for the identification of enzymes that can break down the junk in a physiological setting, and the engineering of these enzymes such that they can break down the target in the correct organelle of the correct cell without appreciable collateral damage to healthy cells or tissue.

Methuselah Foundation and SENS Research Foundation did excellent work in establishing this program nearly a decade ago. They successfully identified a number of candidate enzymes that could break down the molecular junk, but reported that the targeting systems evaluated failed to deliver these enzymes to the appropriate organelles and cells. My group reevaluated these findings, and discovered that these findings were flawed. The delivery failure could be entirely attributed to a subtle, yet highly significant difference between how the target cells behave outside of the body as compared to inside the body. It turned out that the approach was in fact valid, it was the cell based assay that had been used that was flawed. This discovery was striking enough that SENS Research Foundation provided Ichor with funding and a material and technology transfer agreement to reassess the technology, and over $700,000 in directed program investments and grants have been received in the last year or two.

You recently completed a round of funding for the AMD work; what is the plan for the next year or so?

The new funds will allow us to develop a portfolio of enzyme therapy candidates to treat AMD. We will obtain critical data necessary to secure follow-on investment including in vitro studies (cell culture studies to confirm mechanism of action and cytotoxicity) and pivotal proof-of-concept in vivo studies, such as toxicity, PK/PD (how long the enzyme stays in the body and where), and efficacy. We will also be restructuring the company (reincorporating an IP holding company in Delaware, ensuring all contracts are up to date and audited) and ensuring our IP position is on solid footing (licensing in several related patents from existing collaborators, and filing several provisional patents from our intramural work). Collectively, we believe these efforts will position us to obtain series A for investigational new drug (IND) enabling pre-clinical studies.

You’ve been involved in the rejuvenation research community for quite some time now. What is your take on the bigger picture of SENS and the goal of ending aging?

This is a loaded question. What I can say is that the medical establishment has made great progress in the treatment of infectious disease through the development of antibiotics, vaccines, and hygiene programs. However, similar progress has not been realized for the diseases of old age, despite exorbitant expenditures. I have chosen to work in this space because I think a different approach is necessary, and it is here that I believe my companies and I can be the most impactful. I think SENS provides a good framework within which to ask and answer questions.

What do you see as the best approach to getting nascent SENS technologies like this one out of the laboratory and into the clinic?

We need more people who fully understand, in a highly detailed way, what a real translational path looks like. To take on projects like this, being a good scientist is not enough. We need people who can speak business, science, medicine, and legal, and apply these diverse disciplines to a well articulated, focused product or problem. There is no shortage of people who partially understand some of these, but the details are not somewhat important – they are all that matter for success in this space.

Another area is for investors. Some of the projects that come across my desk for review are truly abysmal, yet I have seen projects that are clearly elaborate hoaxes or outright scams (to anyone who has stepped foot in a laboratory) get funded to the tune of hundreds of thousands of dollars or more. While it is perfectly reasonable for high net worth individuals to gamble on moon shots in the anti-aging space (and I am ever grateful for the investors who have taken such a gamble on us) even aggressive development strategies should have some basis in reality. This is especially true as more and more high tech and internet investors move into the space.

If this works stupendously well, what comes next for Ichor Therapeutics?

I really want to get back into stem-cell research, but I basically need a blank check and a strong knowledge of the regulatory path to clinic before I feel comfortable moving into the space. A successful AMD exit would accomplish both of these goals, and position us to pivot to cell-based therapies.

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries.
***
This work is reproduced here in accord with a Creative Commons Attribution license. It was originally published on FightAging.org.
Aubrey de Grey at the Launching Longevity Panel, and Announcing Acceptance of the First Paper to be Published on MitoSENS Research – Article by Reason

Aubrey de Grey at the Launching Longevity Panel, and Announcing Acceptance of the First Paper to be Published on MitoSENS Research – Article by Reason

Comments 1 comment
The New Renaissance HatReason
******************************

Today I’ll direct your attention to a couple of videos, thematically linked by the presence of Aubrey de Grey, cofounder of the SENS Research Foundation and tireless advocate for progress towards working rejuvenation therapies. For the first of the videos, de Grey recently took part in a panel discussion involving representatives of the biotechnology industry, the research establishment, and venture capital community, with the topic being the coming development of a new industry that will develop therapies to extend healthy life and turn back aging. That industry has barely started to form its earliest and smallest stage today, as the first lines of rejuvenation research reach the point of commercial viability. There are a few startups and a lot of deep pockets yet to be convinced that this is going somewhere – though the commentary in the panel is encouraged, considering those involved.

The recent Rejuvenation Biotechnology 2016 conference hosted by the SENS Research Foundation was more along the same lines, focused on creating a foundation for the near future industry that will build and provide rejuvenation therapies. The purpose of the conference series is to help smooth the way for these treatments to move rapidly from the laboratory to the clinic, to build the necessary relationships, manage expectations, and pull in the additional support needed to make best possible progress. The conference was livestreamed over the past couple of days, and at one point Aubrey de Grey announced the just-then-and-there acceptance of the first scientific publication for the MitoSENS team at the SENS Research Foundation. They are presently in the lead, at the cutting edge, among the few groups working on the project of copying mitochondrial genes into the cell nucleus to protect them from the damage of aging. Ultimately, copying all thirteen genes should completely remove the contribution of mitochondrial damage to degenerative aging, as mitochondria will no longer become dysfunctional as their local DNA is damaged. They will get the proteins they need from the cell nucleus instead. It is a worthy project, and it is always welcome to see progress on this front.

Launching Longevity: Funding the Fountain of Youth

 

Can technology make human longevity a reality? As the pace of discovery accelerates, scientists and entrepreneurs are closing in on the Fountain of Youth. Disrupting the aging process by hacking the code of life, promises better health and longer maximum lifespans. With many layers of complexity from science to ethics, there are still skeptics placing odds against human longevity. Venture capitalists are betting on success; putting big money on the table to fund longevity startups. Google/Alphabet and drugmaker AbbVie have invested $1.5 billion on Calico, while Human Longevity Inc. recently raised $220 million from their Series B funding round. Complementing traditional venture investment, VCs like Peter Thiel and Joon Yun have established foundations and prizes to accelerate the end of aging. Why are VCs suddenly investing heavily in longevity startups? Will extended lifespan be a privilege of the wealthy or will the benefits be accessible to all? How long before these well-funded startups bring viable products to market?

 

Aubrey de Grey Announces Progress in MitoSENS

 

Ok everybody, before I introduce the next session I just wanted to make a very small, brief, but very welcome announcement. Literally half an hour ago we received some extremely good scientific news. Those of you who have been following SENS research since before the SENS Research Foundation itself even existed will know that, about a decade ago, the very first project, the very first research program that we were able to initiate – with the help of, especially, the initial donation of Peter Thiel – was to make mitochondrial mutations harmless by essentially putting backup copies of the mitochondrial DNA into the nuclear genome, modified in such way of course that the encoded proteins would be colocated back into the mitochondria to do their job. This is an idea that was first put forward more than 30 years ago, but it is an idea that despite quite a bit of initial effort, nobody was able to make work. When I first came across this concept, in fact I’d thought of it myself, it’s a pretty obvious idea really, I came to the conclusion that a lot of the despair and despondency and pessimism about this approach was premature, and that it was worth having another go, and so that was the very first project we decided to fund.

Suffice to say that it has not been quite as easy as I was hoping to make progress in that space, but progress has now been made, step by step, over the past several years, with the help especially of the absolutely amazing team we have at the research center, who work on this, headed by Matthew O’Connor. Amutha Boominathan is the number two on the team, and is absolutely indispensable, I’ve no idea where we’d be without her. So, what’s happened half an hour ago is that for the very first time in the entire history of this project, we have got far enough to have a paper accepted in a very nice journal, Nucleic Acids Research, which reports on our progress in this area. The headline result in this paper is that we are the first team ever to get two of the proteins encoded by genes in the mitochondrial DNA simultaneously functioning in the same cell line, and of course – two is equivalent to infinity for mathematicians, you know that, right? – this is extremely heartening news, and I just wanted to let you all know, thank you.

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries.
This work is reproduced here in accord with a Creative Commons Attribution license. It was originally published on FightAging.org.
Our Media-Driven Epistemological Breakdown – Article by Bill Frezza

Our Media-Driven Epistemological Breakdown – Article by Bill Frezza

Comments 0 Comment
The New Renaissance HatBill Frezza
******************************

How do we know what we know? Philosophers have pondered this question from time immemorial. Julian Jaynes, in his classic book, The Origin of Consciousness in the Breakdown of the Bicameral Mind, speculates that before the development of modern human consciousness, people believed they were informed by voices in their heads. Today, an alarming number of people are responding to voices on the Internet in similarly uncritical fashion.

As Jesuit scholar John Culkin pointed out in his seminal 1967 Saturday Review article, “A Schoolman’s Guide to Marshall McLuhan,” “We shape our tools and, thereafter, they shape us.” Examining history through this lens, one can identify seven great epochs in mankind’s intellectual and social evolution.  Each is characterized by the way a new technology changed not only how we think about the world, but our actual thought processes. These are:

1) Spoken language, which first led to the primacy of mythology;

2) Written language, which bequeathed to us holy books and the world’s great religions;

3) The printing press, which spread literacy to the elites who went on to birth the nation state, the Reformation, the Enlightenment, and the U.S. Constitution;

4) The telegraph, which transformed pamphlets and broadsheets into modern newspapers, whose agenda-setting influence goaded America to “Remember the Maine” and become an imperialist power;

5) Radio, which placed broadcast propaganda at the service of central planners, progressives, and tyrants;

6) Television, which propelled the rising tide of the counterculture, environmentalism, and globalism; and

7) The Internet, a nascent global memory machine that puts the Library of Alexandria to shame, yet fits in everyone’s pocket.

Reason’s primacy is a fragile thing.

At each transition, the older environment and way of thinking does not disappear. Rather, it adopts an extreme defensive crouch as it attempts to retain power over men’s minds. It is the transition from the Age of Television to the Age of the Internet that concerns us here, as it serves up an often-toxic brew of advocacy and click-bait journalism competing to feed the masses an avalanche of unverifiable information, often immune to factual or logical refutation.

Rational epistemology holds that reason is the chief test and source of knowledge, and that each of us is not just capable of practicing it, but is responsible for doing so. Reason flowered when the Enlightenment overturned the ancient wisdom of holy books, undermining the authority of clerics and the divine right of kings. Wherever reason is widely practiced and healthy skepticism is socially accepted, error becomes self-correcting (rather than self-amplifying, as under a system based on superstition), as new propositions are tested, while old propositions get reexamined as new facts come to light.

So now that the voices have returned to our heads, we are inadequately prepared to defend against them.

Yet, reason’s primacy is a fragile thing. As increasingly potent electronic media confer influence on new voices, formerly-dominant media and governing elites fight a rearguard action to regain their status as ultimate arbiters of knowledge and what matters. Goebbels proved that a lie repeated loudly and frequently in a culture that punished skepticism became accepted as truth. We all know how that turned out.

Revulsion at the carnage of the Second World War crested with the counterculture revolution driven by the first TV generation. By the time the dust settled, its thought leaders had grabbed control of the academy, reshaping it along postmodern lines that included an assault on language that critics dubbed political correctness. This was intentionally designed to constrain what people can think by restraining what they can say. The intention may have been to avert a repeat of the horrors of the 20th century, but the result was to strip much of the educated populace of the mental tools needed to ferret out error.

So now that the voices have returned to our heads, we are inadequately prepared to defend against them. Digitally streamed into every nook and cranny of our ubiquitously connected lives, these voices are filtered by our own self-reinforcing preferences and prejudices, becoming our own in the process. The result is an ongoing series of meme-driven culture wars where the shouting only gets louder on all sides.

So we come back to the question: How do we know what we know?

What causes crime? Is autism linked to vaccines? Should GMOs be banned? Is global warming “settled science”? These are more than factual questions. Responses to them signal identification with an array of ever more finely differentiated identity groups set at each other’s throats. For those who wish to divide and rule, that’s the whole point.

In a cruel irony, this global outbreak of media-induced public schizophrenia has even empowered jihadists bent on taking the world back to the 10th century using the idea-spreading tools of the Internet to challenge a Western Civilization rapidly losing its mojo.

So we come back to the question: How do we know what we know? At the present time, we don’t. And therein lies the problem.

Bill Frezza

Bill Frezza is a fellow at the Competitive Enterprise Institute and the host of RealClear Radio Hour.

This article was originally published on FEE.org. Read the original article.

Towards a Greater Knowledge of Mitochondrial DNA Damage in Aging – Article by Reason

Towards a Greater Knowledge of Mitochondrial DNA Damage in Aging – Article by Reason

Comments 0 Comment
The New Renaissance HatReason
******************************

Today I’ll point out a very readable scientific commentary on mutations in mitochondrial DNA (mtDNA) and the importance of understanding how these mutations spread within cells. This is a topic of some interest within the field of aging research, as mitochondrial damage and loss of function is very clearly important in the aging process. Mitochondria are, among many other things, the power plants of the cell. They are the evolved descendants of symbiotic bacteria, now fully integrated into our biology, and their primary function is to produce chemical energy store molecules, adenosine triphosphate (ATP), that are used to power cellular operations. Hundreds of mitochondria swarm in every cell, destroyed by quality control processes when damaged, and dividing to make up the numbers. They also tend to promiscuously swap component parts among one another, and sometimes fuse together.

Being the descendants of bacteria, mitochondria have their own DNA, distinct from the nuclear DNA that resides in the cell nucleus. This is a tiny remnant of the original, but a very important remnant, as it encodes a number of proteins that are necessary for the correct operation of the primary method of generating ATP. DNA in cells is constantly damaged by haphazard chemical reactions, and equally it is constantly repaired by a range of very efficient mechanisms. Unfortunately mitochondrial DNA isn’t as robustly defended as nuclear DNA. Equally unfortunately, some forms of mutation, such as deletions, seem able to rapidly spread throughout the mitochondrial population of a single cell, even as they make mitochondria malfunction. This means that over time a growing number of cells become overtaken by malfunctioning mitochondria and fall into a state of dysfunction in which they pollute surrounding tissues with reactive molecules. This can, for example, increase the level of oxidized lipids present in the bloodstream, which speeds up the development of atherosclerosis, a leading cause of death at the present time.

The question of how exactly some specific mutations overtake a mitochondrial population so rapidly is still an open one. There is no shortage of sensible theories, for example that it allows mitochondria to replicate more rapidly, or gives them some greater resistance to the processes of quality control that normally cull older, damaged mitochondria. The definitive proof for any one theory has yet to be established, however. In one sense it doesn’t actually matter all that much: there are ways to address this problem through medical technology that don’t require any understanding of how the damage spreads. The SENS Research Foundation, for example, advocates the path of copying mitochondrial genes into the cell nucleus, a gene therapy known as allotopic expression. For so long as the backup genes are generating proteins, and those proteins make it back to the mitochondria, the state of the DNA inside mitochondria doesn’t matter all that much. Everything should still work, and the present contribution of mitochondrial DNA damage to aging and age-related disease would be eliminated. At the present time there are thirteen genes to copy, a couple of which are in commercial development for therapies unrelated to aging, another couple were just this year demonstrated in the lab, and the rest are yet to be done.

Still, the commentary linked below is most interesting if you’d like to know more about the questions surrounding the issue of mitochondrial DNA damage and how it spreads. This is, as noted, a core issue in the aging process. The authors report on recent research on deletion mutations that might sway the debate on how these mutations overtake mitochondrial populations so effectively.

Expanding Our Understanding of mtDNA Deletions

A challenge of mtDNA genetics is the multi-copy nature of the mitochondrial genome in individual cells, such that both normal and mutant mtDNA molecules, including selfish genomes with no advantage for cellular fitness, coexist in a state known as “heteroplasmy.” mtDNA deletions are functionally recessive; high levels of heteroplasmy (more than 60%) are required before a biochemical phenotype appears. In human tissues, we also see a mosaic of cells with respiratory chain deficiency related to different levels of mtDNA deletion. Interestingly, cells with high levels of mtDNA deletions in muscle biopsies show evidence of mitochondrial proliferation, a compensatory mechanism likely triggered by mitochondrial dysfunction. In such circumstances, deleted mtDNA molecules in a given cell will have originated clonally from a single mutant genome. This process is therefore termed “clonal expansion.”

The accumulation of high levels of mtDNA deletions is challenging to explain, especially given that mitophagy should provide quality control to eliminate dysfunctional mitochondria. Studies in human tissues do not allow experimental manipulation, but large-scale mtDNA deletion models in C. elegans have proved to be helpful, showing some conserved characteristics that match the situation in humans, as well as some divergences. Researchers have used a C. elegans strain with a heteroplasmic mtDNA deletion to demonstrate the importance of the mitochondrial unfolded protein response (UPRmt) in allowing clonal expansion of mutant mtDNAs to high heteroplasmy levels. They demonstrate that wild-type mtDNA copy number is tightly regulated, and that the mutant mtDNA molecules hijack endogenous pathways to drive their own replication.

The data suggests that the expansion of mtDNA deletions involves nuclear signaling to upregulate the UPRmt and increase total mtDNA copy number. The nature of the mito-nuclear signal in this C. elegans model may have been the transcription factor ATFS-1 (activating transcription factor associated with stress-1), which fails to be imported by depolarized mitochondria, mediates UPRmt activation by mtDNA deletions. A long-standing hypothesis proposes that deleted mtDNA molecules clonally expand because they replicate more rapidly due to their smaller size. To address this question, researchers examined the behavior of a second, much smaller mtDNA deletion molecule. They found no evidence for a replicative advantage of the smaller genome, and clonal expansion to similar levels as the larger deletion. In human skeletal muscle, mtDNA deletions of different sizes also undergo clonal expansion to the same degree. Furthermore, point mutations that do not change the size of the total mtDNA molecule also successfully expand to deleterious levels, indicating that clonal expansion is not driven by genome size. Thus, similar mechanisms may be operating across organisms. In the worm, this involves mito-nuclear signaling and activation of the UPRmt.

There is some debate over interpretation of results. One paper indicates that UPRmt allows the mutant mtDNA molecules to accumulate by reducing mitophagy. Another demonstrates that the UPRmt induces mitochondrial biogenesis and promotes organelle dynamics (fission and fusion). Both papers show that by downregulating the UPRmt response, mtDNA deletion levels fall, which may allow a therapeutic approach in humans. Could there be a similar mechanism in humans, especially since some features detected in C. elegans are also present in human tissues, including the increase in mitochondrial biogenesis and the lack of relationship between mitochondrial genome size and expansion? It is likely that there will be a similar mechanism to preserve deletions since, as in the worm, deletions persist and accumulate in human tissues, despite an active autophagic quality-control process. Although the UPRmt has not been characterized in humans as it has in the worm, and no equivalent protein to ATFS-1 has been identified in mammals, proteins such as CHOP, HSP-60, ClpP, and mtHSP70 appear to serve similar functions in mammals as those in C. elegans and suggest that a similar mechanism may be present.

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries.
This work is reproduced here in accord with a Creative Commons Attribution license. It was originally published on FightAging.org.
Crowdfunding Longevity Science: An Interview with Keith Comito of Lifespan.io – Article by Reason

Crowdfunding Longevity Science: An Interview with Keith Comito of Lifespan.io – Article by Reason

Comments 0 Comment
The New Renaissance HatReason
******************************

Keith Comito leads the volunteers of the non-profit Life Extension Advocacy Foundation (LEAF) and the crowdfunding initiative Lifespan.io, a site I’m sure you’ve seen at least in passing by now. The LEAF crew have put in a lot of effort to help make fundraisers for rejuvenation research projects a success both last year and this year. Two such crowdfunding campaigns are running right now, firstly senolytic drug research at the Major Mouse Testing Program with just a few days left to go, and in its stretch goals, and secondly the recently launched drug discovery for ALT cancers at the SENS Research Foundation. Both tie in to the SENS portfolio of research programs aimed at effective treatment of aging and all age-related conditions. These are large projects when taken as a whole, but the way forward in this as in all things is to pick out smaller, achievable goals, and set out to get them done. Then repeat as necessary.

I recently had the chance to ask Keith Comito a few questions about Lifespan.io, the state of funding for the interesting end of longevity science, and what he envisages for the years ahead. This is an interesting, revolutionary time for the life sciences, in which progress in biotechnology has made early stage research very cheap. A great deal can be accomplished at the cutting edge of medical science given access to an established lab, administrators who can break out small initiatives from the larger goals, smart young researchers, and a few tens of thousands of dollars. It is an age in which we can all help to advance the research we care about, by collaborating and donating, and it has never been easier to just reach out and talk to the scientists involved. If you haven’t taken a look at Lifespan.io and donated to one of the projects there, then you really should. This is a way to move the needle on aging research, and advance that much closer to effective treatments for the causes of aging.

Quote:

What is the Lifespan.io story in brief? What was the spur that made you come together and decide to do your part in the fight against aging?

Lifespan.io began to take shape at the tail end of 2012, as a result of a loose discussion group based in New York which consisted of citizen scientists such as myself and Dr. Oliver Medvedik, supporters of SENS, as well as a few healthcare practitioners. We began having monthly meetings to discuss what could be done to accelerate longevity research (usually in oddball locations like salad bars or subterranean Japanese restaurants befitting our motley crew) and eventually hit upon the idea of crowdfunding. What drew us to this idea was that it was something tangible: a concrete way to move the needle on important research not only through funds, but through raised awareness. It is fine to talk and rabble-rouse about longevity, but we felt such efforts would be much more effective if they were paired with a clear and consistent call to action – a path to walk the walk, so to speak. As this idea coalesced we formed the nonprofit LEAF to support this initiative, and the rest is history. Not every one from the initial discussions in 2012 remained throughout the intervening years, but we are thankful to all who gave us ideas in those early days of the movement.

I’d like to hear your take on why we have to advocate and raise funds at all – why the whole world isn’t rising up in support of treatments for the causes of aging.

The reasons why people and society at large have not prioritized anti-aging research thus far are myriad: fear of radical change, a history of failed attempts making it seem like a fools errand, long timescales making it a difficult issue for election-focused politicians to support, etc. The reason I find most personally interesting relates to cognitive bias – specifically the fact that our built-in mental hardware is ill-equipped to handle questions like “do you want to live 100 more years?” If instead you ask the questions “Do you want to be alive tomorrow?” and “Given that your health and that of your loved ones remains the same, do you suspect your answer to the first question will change tomorrow?”, the answers tend to be more positive.

This leads me to conclude that the state of affairs is not necessarily as depressing for our cause as it might appear, and that reframing the issue of healthy life extension in a way that will inspire and unite the broader populace is possible. Aubrey de Grey has spoken about “Longevity Escape Velocity” in relation to the bootstrapping of biomedical research, but I think the same idea applies to the public perception of life extension as well. The sooner we can galvanize the public to support therapies that yield positive results the easier it will become to invite others to join in this great work. It is all about jump starting the positive feedback loop, and that is why we believe rallying the crowd behind critical research and trumpeting these successes publicly is so vitally important.

What the future plans for Lifespan.io and the Life Extension Advocacy Foundation?

In addition to scaling up our ability to run successful campaigns on Lifespan.io, we look forward to improving our infrastructure at LEAF by bringing on some staff members to join the team. LEAF has largely been a volunteer effort thus far, and having the support of a staff will allow us to take on more campaigns as well as further improve the workflow to create and promote them. This will also free me up personally to more actively pursue potential grand slams for the movement, such as collaborations with prominent YouTube science channels to engage the public and policy related goals like the inclusion of a more useful classification of aging in the ICD-11.

Do you have any favored areas in research at the moment? Is there any particular field for which you’d like to see researchers approaching you for collaboration?

Senolytics is certainly an exciting area of research right now (congratulations Major Mouse Testing Program!), and a combination of successful senolytics with stem cell therapies could be a potential game changer. That being said I’d also like to see projects which address the truly core mechanics of aging, such as how damage is aggregated during stem cell division, and the potential differences in this process between somatic and germ cells. How can the germ line renew itself for essentially infinity? The real mystery here is not that we grow old, but how we are born young.

A related question: where do you see aging and longevity research going over the next few years?

In the near future we will likely continue to see the pursuit of compounds which restore bodily systems failing with age to a more youthful state. This will include validating in higher organisms molecules that have shown this sort of promise: rapamycin, metformin, IL-33 for Alzheimer’s, etc. This approach may sound incremental, but it actually signals a great paradigm shift from the old system of mostly ineffective “preventative measures” such as antioxidants. Things like nicotinamide mononucleotide (NMN), IL-33 – if successful these types of therapies can be applied when you are old, and help restore your bodily systems to youthful levels. That would be a pretty big deal.

Funding is ever the battle in the sciences, and especially for aging. Obviously you have strong opinions on this topic. How can we change this situation for the better?

I believe the key to greater funding, both from public and private sources, is to build up an authentic and powerful grassroots movement in support of healthy life extension. Not only can such a movement raise funds directly, but it also communicates to businesses and governments that this is an issue worth supporting. An instructive example to look at here is the work of Mary Lasker and Sydney Farber to bring about the “War on Cancer”. Through galvanizing the public with efforts such as the “Jimmy Fund”, they effected social and political change on the issue, and helped turn cancer from a pariah disease into a national priority. If we all work together to build an inclusive and action-orientated movement, we can do the same.

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries.
***
This work is reproduced here in accord with a Creative Commons Attribution license. It was originally published on FightAging.org.

 

A Most Interesting Data Set Covering the Longevity of Polish Elite Athletes Across Much of the 20th Century – Article by Reason

A Most Interesting Data Set Covering the Longevity of Polish Elite Athletes Across Much of the 20th Century – Article by Reason

Comments 0 Comment
The New Renaissance HatReason
******************************

Today I noticed an open access paper in which the authors examine mortality data for Polish Olympic athletes over the past 90 years or so, and compare it with established historical data for the general population. This blends two topics that are occasionally covered here at Fight Aging!: firstly, the growth in human life expectancy in recent history and its causes, and secondly the topic of how regular exercise and life expectancy interact. It is the present consensus that elite athletes, those at the top of their profession, live longer than the rest of us, but it remains open to debate as to whether this is because more exercise is better, or because very robust people who would have lived longer anyway are more likely to enter the world of professional athletics. Researchers want to map the dose-response curve for exercise, in other words. Even though there is very good, very solid evidence for the benefits of regular moderate exercise versus being sedentary, going beyond that to a more nuanced view of what more or less exercise does for health is a challenging goal given the starting point of statistical snapshots of data from various study populations.

Studying the history of life expectancy isn’t much easier, though there the challenges tend to revolve around the ever-decreasing quality of data as you look further back in time. The 20th century marked transitions from hopeful aspiration to solid accomplishment in all fields of medicine, too many profound advances in the capabilities of medical science and practice to list here. As the decades passed, this important progress focused ever more on treatments for age-related conditions. An individual born in the US in 1900 suffered through the end of the era of poor control of infectious disease, prior to modern antibiotics and antiviral drugs, and likely benefited little from later progress towards better control of heart disease and other common age-related diseases. An individual born in the US in 1950, on the other hand, enjoyed a youth with comparatively little fear of disease, and is probably still alive today, with access to far more capable therapies than existed even a couple of decades ago.

Given all of this, one of the interesting things to note in the analysis of the Polish data is that the elite athletes born in the early 20th century appear to have a lower rate of aging than the general population, as determined by a slower rise in mortality over time, but that this difference between athletes and the average individual is greatly diminished for people born in the latter half of the 20th century. This suggests, roughly, that advances in medicine from 1900 to 1950 had a leveling effect, bringing up the average, preventing early deaths, but doing little to address age-related disease. That said, there is a large variation in results across the range of similar studies, both those that look at the history of longevity, and those that look at populations of athletes at a given time. It is wise to consider epidemiological studies in groups rather than one by one, and look for common themes. Still, this one is a fascinating data set for the way in which it combines historical trends and exercise in the study of aging.

Examining mortality risk and rate of ageing among Polish Olympic athletes: a survival follow-up from 1924 to 2012 – by Yuhui Lin, Antoni Gajewski, and Anna Poznańska

Quote:

A sedentary lifestyle is associated with the onset of chronic diseases including ischaemic heart disease, type-II diabetes and neurodegenerative diseases. Frequent exercise is perceived as a major behavioural determinant for improved life expectancy and a slower rate of ageing. There is little doubt that frequent exercise is beneficial for individuals’ well-being, and an active lifestyle reduces the risk for chronic diseases. However, it is still uncertain whether the rate of ageing decelerates in response to frequent and intense physical exercise. Our attempt is the first empirical study to show the application of a parametric frailty survival model to gain insights into the rate of ageing and mortality risk for Olympic athletes.

Our participants for this parametric frailty survival analysis were Polish athletes who had participated in the Olympic Games from 1924 to 2010. We assumed that these athletes were elite in their preferred sports expertise, and that they were engaged in frequent, if not intense, physical exercise. The earliest recorded year of birth was 1875, and the latest was in 1982; total N=2305; male=1828, female=477. For reliable estimates, mortality improvements by calendar events and birth cohort had to be taken into consideration to account for the advancements made in medicine and technology. After the consideration of mortality improvements and the statistical power for parametric survival analysis, we restricted our analysis to male athletes born from 1890 to 1959 (M=1273). For reliable estimates, we preassigned recruited athletes into two categorical cohorts: 1890-1919 (Cohort I); 1920-1959 (Cohort II).

Our findings suggest that Polish elite athletes in Cohort I born from 1890-1919 experienced a slower rate of ageing, and had a lower risk for mortality and a longer life-expectancy than the general population from the same birth cohort. It is very unlikely that these survival benefits were gained within a short observational time. Therefore, we argue that participation in frequent sports from young adulthood reduces mortality risk, increases life-expectancy and slows the rate of ageing. The age-specific mortality trajectories of Cohort I elite athletes also suggest frequent exercise can decelerate the rate of ageing by 1% with an achievement of threefold risk reduction in mortality. In comparison with those of the general population, the differences in energy expenditure, behavioural habits, body mass and sports expertise were likely to be the contributing factors to the higher variance in lifespan among elite athletes.

In Cohort II, the estimated rate of ageing is highly similar between elite athletes and the general population, which contradicts our estimates for Cohort I. This may be attributed to mortality improvements from year 1920 onwards in Poland. These mortality improvements have changed individuals’ susceptibilities for different causes of death, which has resulted in an increased variation in lifespan both in the general population and for elite athletes. Interestingly, the comparison of the rate of ageing of elite athletes in Cohort I and II shows a similar rate of ageing. Among the elite athletes, the estimates suggest that Cohort II individuals benefited from a 50% mortality risk reduction as compared with individuals born in Cohort I. The estimated overall mortality risk of the Polish general population is 29% lower in Cohort II than in I.

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries.
This work is reproduced here in accord with a Creative Commons Attribution license. It was originally published on FightAging.org.