Fight Aging! Newsletter, November 28th 2016

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

This content is published under the Creative Commons Attribution 3.0 license. You are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

To subscribe or unsubscribe please visit: https://www.fightaging.org/newsletter/

Contents

  • Become a SENS Patron Before the Year Ends: Another 12,000 is Added to the Challenge Fund, and We Need Your Help to Meet that Goal
  • Cryonics in the News of Late
  • Predicting the Order of Arrival of the First Rejuvenation Therapies
  • Some Adaptive Immune Cells Become More Innate-Like in the Aged Immune System
  • Linking Excess Fat Tissue, Immune Dysfunction, and Cellular Senescence in Aging
  • Latest Headlines from Fight Aging!
    • A Look at Scaling Up the Tissue Engineering of Larger Blood Vessels
    • Mitochondrial Antioxidant SkQ1 as a Treatment for Age-Related Dry Eye Syndrome
    • Manipulating Existing Methods of Cellular Quality Control to Clear Mutant Mitochondria
    • Dementia Risk is Declining, for Reasons Yet to be Conclusively Established
    • Evidence to Suggest Parabiosis Effects Result from Dilution of Damage
    • Zebrafish Extracellular Matrix Produces Enhanced Regeneration in Mouse Hearts
    • Growing Intestinal Tissue Organoids with Functional Nerves
    • The Gender Longevity Gap is Consistent Over Populations and Time
    • An Illustration of the Complexity of Genetic Contributions to Longevity
    • Mapping RNA in Search of the Mechanisms of Bat Longevity

Become a SENS Patron Before the Year Ends: Another 12,000 is Added to the Challenge Fund, and We Need Your Help to Meet that Goal
https://www.fightaging.org/archives/2016/11/become-a-sens-patron-before-the-year-ends-another-12000-is-added-to-the-challenge-fund-and-we-need-your-help-to-meet-that-goal/

The end of year fundraiser for SENS rejuvenation research progresses apace. We are helping to fund the work needed to produce actual, working rejuvenation therapies soon enough to matter, treatments that can target and repair the fundamental causes of aging. Aging is caused by a few forms of molecular damage that accrue in cells and tissues, a sort of slow biological wear and tear that results from the normal operation of metabolism. Given the right lines of research, that damage can be repaired, and thus the clock turned back, age-related disease prevented or effectively treated. Those research programs are outlined in the SENS vision, and have been underway for some years now, making steady progress with the support of everyday philanthropists like you and I.

At the start of November, Josh Triplett and Fight Aging! put up a 24,000 challenge fund for new SENS Patrons: everyone who signs up before the end of the year to make a regular monthly donation to the SENS Research Foundation will have the next year of donations matched. I'm pleased to announce that this past weekend, Christophe and Dominique Cornuejols stepped up to contribute another 12,000 to the fund. You might recall that they also provided a matching fund to help in the last days of the universal cancer therapy crowdfunding effort earlier this year. It is a privilege to have had the support of these folk over the past few years of Fight Aging! fundraisers.

The SENS Patron challenge fund was 24,000, and is now 36,000. That means we're looking for more SENS Patrons to take the plunge and help to extend and broaden the research success produced by the SENS Research Foundation and their allies in past years. We live in exciting times when it comes to medicine for human rejuvenation, with senescent cell clearance therapies now in well-funded clinical development and other lines of research threatening to follow in the years ahead. The transition is underway from the medicine of the past, that did not in any meaningful way address the molecular damage that causes aging and age-related disease, to the medicine of the future, in which that damage is targeted for repair. We will have longer, healthier lives thanks to the efforts of SENS advocates and researchers, and thanks to the many people whose charitable donations have allowed this work to take place at all.

It has been a tough job to bootstrap a new field of medicine from scratch, in the face of all of those who said it couldn't be done or shouldn't be done. There are certainly fewer naysayers now that the wheel is beginning to turn, however, and now that the first rejuvenation research startup companies are working on bringing therapies to the clinic. Researchers talk openly about targeting the processes of aging, and there is enthusiasm for progress in many parts of the research and development communities. This is the time for advocates and donors to push harder, to build atop present success, to lay the foundations for the next set of treatments to emerge in the years ahead. There are seven classes of cell and tissue damage involved in aging, and only two or three of those could be said to be proceeding at a productive pace today: senescent cell clearance, stem cell research, and some forms of amyloid clearance. The others are just as important, but still languishing, with comparatively little funding, and yet to reach the tipping point that senescent cell clearance reached in the past few years. When that point arrives for a specific line of research it becomes a pretty fast ride from a few groups in the laboratory to multiple venture funded companies working on clinical applications of longevity science, but getting there is up to us.

To a first approximation no-one cares about funding fundamental medical research, and the most important work is near always heavily funded by visionaries and philanthropists, rather the established funding institutions. It is really, really hard to raise funding for radical new approaches in medicine - until the researchers can prove that they work. See what David Spiegel of the noted Spiegel Laboratory at Yale had to say on that topic, for example:

The SENS Research Foundation funding has been critical to our work studying and developing methods to reverse the effects of advanced glycation end-products (AGEs) in aging. AGEs are non-enzymatic modifications that build up on proteins as people age, leading to inflammation and tissue damage. Early on, our lab focused significant effort on developing the first total synthesis of glucosepane - a major AGE cross-link found in human tissues - but we were unable to find funding from any of the traditional sources. The SENS Research Foundation came to our aid, and supported this research for over 5 years. In 2015, our glucosepane synthesis efforts were published in Science, and lay a foundation for developing drugs capable of detecting and reversing tissue damage in aging. We are deeply grateful to the SENS Research Foundation and Fight Aging! for all of their support and look forward to exciting, life-extending work to come!

The work of the Spiegel Laboratory will form the foundation of an approach to treat aging that will be just as important as senescent cell clearance. But like so many vital lines of research related to the future of rejuvenation therapies, and like so many vital lines of research in the broader field of medicine, funding just can't be found through the existing establishment. That is why our fundraisers and our acts of advocacy are so very important. The future is in our hands: we are the ones who raise up the lantern and shine a light on the research and development that must happen; who call for assistance and vote with our wallets; who raise the profile of this work; who provide the funding needed for prototypes and further evidence; and who start the ball rolling. When high net worth individuals join in, when the institutions finally pay attention, when the venture capitalists fund companies, it is because we took action, and because we did our part to show the way. So join in!

Cryonics in the News of Late
https://www.fightaging.org/archives/2016/11/cryonics-in-the-news-of-late/

Cryonics is the low-temperature preservation of at least the brain following death, leaving open the possibility of restoration to life in a future in which molecular nanotechnology and total control of cellular biochemistry are mature industries. As individuals, each of us is the data of the mind, no more, no less, and that data is stored in the form of fine physical structures, most likely those of the synapses connecting neurons. If that structure is preserved sufficiently well, then the individual is not yet gone - only ceased for the moment. Early cryopreservations involved straight freezing to liquid nitrogen temperatures, and this likely caused great damage to the structures of the brain due to ice crystal formation. Modern cryopreservations use cryoprotectants and staged cooling to achieve vitrification of tissues with minimal ice crystal formation. There the degree of damage is much reduced, contingent on sufficient perfusion of cryoprotectant and the quality of the other aspects of the process. These technologies are also under development by groups in the organ transplantation and tissue engineering communities: reversible vitrification of organs would solve a great many logistical problems. From the present state of the science, that goal isn't very far distant. Proof of concept vitrification, thawing, and transplantation of mammalian organs has taken place in the laboratory. Even without present reversibility, however, the merits of cryonics stand: people who are preserved are not dead and gone, just dead, with a chance to return. A chance of unknown size, yes, but that is a big improvement over the grave and certain oblivion.

Cryonics suffers from being a small industry. People encountering the concept for the first time tend look at it askance because it is a small community and thus not the usual end of life choice. Then they make up reasons in their own minds as to why it won't work, or is stupid, or illogical, or otherwise wrong, simply because it is not the norm. It takes multiple exposures to a topic for most people to come around and actually engage with what is known rather than with their own knee-jerk reaction to the topic. In the normal run of things, however, few people actually encounter the ideas of cryonics; it doesn't get all that much press, and since it is such a small industry and surrounding community, few people encounter those involved as they make their way through life. Thus public awareness and understanding of the long-standing cryonics industry seems to advance by a series of infrequent great leaps rather than ongoing incremental gains, each such leap driven by the high-profile cryopreservation of a sympathetic or noted individual that attracts a short-lived mob of press attention. First there is a flood of commentary from those who know next to nothing of cryonics and are quick to condemn it for being different, then a following wave of more thoughtful commentary, for and against, and finally some few of the many people who read the coverage choose to dig further, peruse some of the mountain of literature written on cryonics over the past 40 years, and conclude that cryonics does make sense and is a good idea. So the community of supporters and those signed up as members of a cryonics organization grows a little.

The latest leap forward was spurred by the cryopreservation of a terminally ill young lady in the UK, unusual for its surrounding legal case regarding consent and self-determination. The UK has a cryonics support organization, as is the case for many countries, but like most parts of the world lacks a cryonics provider. This may be why so much of the initial commentary has been from those fairly new to the idea, and has been unusually hostile in tone when compared to the media attention of the past five years or so. Being the UK, there is also a considerable focus on regulation, since the bias over there, in the media at least, is very much towards the idea that nothing must ever happen without government involvement - all that is not explicitly allowed is forbidden, any new endeavor must be quickly regulated by a new government office, and so forth. Sadly the US has been heading in that direction quite energetically since the turn of the century; it has been a sad thing to watch taking place. Cultural differences aside, many cryopreservations are carried out under difficult circumstances, and this was one of them. The ideal preservation takes place at the cryonics provider location, or very close by, within a known window of time, and cooldown is rapid following death so as to minimize damage. Departures from that ideal have a cost, both monetary and in the quality of the preservation, but the people involved here by all accounts did the best possible under the circumstances, hampered by the existing regulatory environment that prevents near every possible approach that could make things easier, cheaper, and more reliable.

Below find a very small selection of the recent attention given to this case. There is a lot more out there, if you are interested enough to go looking, ranging from ignorant and hostile to thoughtful and considered. The incorrect term "cryogenics" is bandied around, as is the mistaken idea that cryopreservation involves freezing: the press is ever haphazard when it comes to accuracy, and it doesn't become much better if you glance at what the wisdom of the crowds produced at social news sites in this case. Ultimately this matter, just as any cryopreservation, boils down to issues of self-determination and responsibility for the self. Sadly this is a topic that many members of our society, and especially those in the media and positions of power, seem to find offensive and undesirable: the idea that people can make decisions for themselves, and that those decisions should be respected. But we live in a world in which there is no choice so personal that it will not be interfered with by regulators and lawmakers, and that seems true whether or not the individual is young enough to be considered by those with power effectively the property of his or her parents. (Which is an entirely different iniquity in and of itself). As adults with a lifetime of experience people have just as much trouble in matters of self-determination at the end of life. Witness the political and legal battles over euthanasia, for example, in which childhood is extended indefinitely and the uncaring minions of the state take on the role of distant and forbidding parents. How free are we, really, when it is declared illegal to decide on matters of our own bodies and our own lives, and those who help will be jailed for the crime of compassionate if they are found out?

14-year-old girl who died of cancer wins right to be cryogenically frozen

A 14-year-old girl who said before dying of cancer that she wanted a chance to live longer has been allowed by the high court to have her body cryogenically frozen in the hope that she can be brought back to life at a later time. The court ruled that the teenager's mother, who supported the girl's wish to be cryogenically preserved, should be the only person allowed to make decisions about the disposal of her body. Her estranged father had initially opposed her wishes. During the last months of her life, the teenager, who had a rare form of cancer, used the internet to investigate cryonics. She sent a letter to the court: "I have been asked to explain why I want this unusual thing done. I'm only 14 years old and I don't want to die, but I know I am going to. I think being cryo-preserved gives me a chance to be cured and woken up, even in hundreds of years' time. I don't want to be buried underground. I want to live and live longer and I think that in the future they might find a cure for my cancer and wake me up. I want to have this chance. This is my wish."

The judge wrote: "I was moved by the valiant way in which she was facing her predicament. The scientific theory underlying cryonics is speculative and controversial, and there is considerable debate about its ethical implications. On the other hand, cryopreservation, the preservation of cells and tissues by freezing, is now a well-known process in certain branches of medicine, for example the preservation of sperm and embryos as part of fertility treatment. Cryonics is cryopreservation taken to its extreme." The judge said the girl's family was not well off but that her mother's parents had raised the money. A voluntary UK group of cryonics enthusiasts, who were not medically trained, had offered to help make arrangements. Co-operation of a hospital was required. The hospital trust in the case was willing to help although it stressed it was not endorsing cryonics. "On the contrary, all the professionals feel deep unease about it," the judge said.

The Human Tissue Authority (HTA), which regulates organisations which remove, store and use human tissue, had been consulted but said it had no remit to intervene in such a case. "The HTA would be likely to make representations that activities of the present kind should be brought within the regulatory framework if they showed signs of increasing," the judge said. The HTA said: "We are gathering information about cryopreservation to determine how widespread it is currently, or could become in the future, and any risks it may pose to the individual, or public confidence more broadly. We are in discussion with key stakeholders on the possible need for regulatory oversight." The government may need to intervene in future, the judge said: "It may be that events in this case suggest the need for proper regulation of cryonic preservation in this country if it is to happen in future."

Cryonics debate: 'Many scientists are afraid to hurt their careers'

Vital interrogation of the science behind cryogenically freezing humans is being stifled because scientists fear being ostracised and ridiculed, according to a leading researcher in the field. The cryobiologist Ramon Risco said scientists risked damaging their careers and being excluded from scientific societies if they worked on cryonics, the controversial science used last month to freeze the body of a 14-year-old cancer victim. "There is an enormous 'stigma bias' to the conversation about cryonics among scientists. For scientists who would like to discuss it open-mindedly it tends to significantly hurt their career - in fact can potentially even get them kicked out of their scientific societies."

Prof Anders Sandberg, a research fellow at the Future of Humanity Institute at Oxford University, said scientists reliant on grants and looking for tenures might exercise self-censorship. "Many young scientists are afraid to hurt their careers. Talking about the future can be very career-limiting. Being seen to be eccentric in the wrong way is frowned upon." Cryonics enthusiasts argue that the stigma surrounding the area could leave people vulnerable to unscrupulous companies ready to fill the void left by science. Tim Gibson of the non-profit group Cryonics UK, which prepared the 14-year-old's body for transportation to the freezing facility in Michigan, said the group, all of whose staff are volunteers, would welcome regulation. "The danger for us is that as the idea gets more publicity, companies wanting to make a profit could spring up and damage us by [taking advantage of clients]."

Those interested in the area who were hopeful that scientific developments could see the reanimation of humans who had been cryogenically frozen would continue to work under the radar, said Risco. He added that "unconventional concepts" such as in vitro fertilisation, space travel and organ transplantation had all suffered "initial bias". "We don't need to start making a big polemic. We will keep on working on organ cryopreservation, no one will call us crazy and eventually we will end up with a solution for the whole body."

Court cryonics ruling is just common sense

Honestly, these cryonics stories are driving me mad. As someone with terminal cancer (and ignoring the fact that I find the description in your articles of people like myself as "cancer victims" to be teeth-grindingly irritating) I feel everyone is ignoring the fact that a young woman looked into her future and saw the denial of everything she was promised. She was denied boyfriends, university, a job, marriage, children, life... and she was not ready to give up on those promises. She didn't want to die. None of us does. I'm grateful that the judge had the good sense to realise this was not about whether cryonics worked, but her own hopes for the future. Reading some pieces lately it seems that while we'll arrange bungee-jumping days out for the terminally ill, how one disposes of one's own corpse is a step too far in giving the dying what they're asking for.

Predicting the Order of Arrival of the First Rejuvenation Therapies
https://www.fightaging.org/archives/2016/11/predicting-the-order-of-arrival-of-the-first-rejuvenation-therapies/

The first rejuvenation therapies to work well enough to merit the name will be based on the SENS vision: that aging is at root caused by a few classes of accumulated cell and tissue damage, and biotechnologies that either repair that damage or render it irrelevant will as a result produce rejuvenation. Until very recently, no medical technology could achieve this goal, and few research groups were even aiming for that outcome. We are in the midst of a grand transition, however, in which the research and development community is finally turning its attention to the causes of aging, understanding that this is the only way to effectively treat and cure age-related disease. Age-related diseases are age-related precisely because they are caused by the same processes of damage that cause aging: the only distinctions between aging and disease are the names given to various collections of symptoms. All of frailty, disease, weakness, pain, and suffering in aging is the result of accumulated damage at the level of cells and protein machinery inside those cells. Once the medical community becomes firmly set on the goal of repairing that damage, we'll be well on the way to controlling and managing aging as a chronic condition - preventing it from causing harm to the patient by periodically repairing and removing its causes before they rise to the level of producing symptoms and dysfunction. The therapies of the future will be very different from the therapies of the past.

The full rejuvenation toolkit of the next few decades will consist of a range of different treatments, each targeting a different type of molecular damage in cells and tissues. In this post, I'll take a look at the likely order of arrival of some of these therapies, based on what is presently going on in research, funding, and for-profit development. This is an update to a similar post written four years ago, now become somewhat dated given recent advances in the field. Circumstances change, and considerable progress has been made in some lines of research and development.

1) Clearance of Senescent Cells

It didn't take much of a crystal ball four years ago to put senescent cell clearance in first place, the most likely therapy to arrive first. All of the pieces of the puzzle were largely in place at that time: the demonstration of benefits in mice; potential means of clearance; interested research groups. Only comparatively minor details needed filling in. Four years later no crystal ball is required at all, given that Everon Biosciences, Oisin Biotechnologies, SIWA Therapeutics, and UNITY Biotechnology are all forging ahead with various different approaches to the selective destruction of senescent cells. No doubt many groups within established Big Pharma entities are also taking a stab at this, more quietly, and with less press attention. UNITY Biotechnology has raised more than 100 million to date, demonstrating that there is broad enthusiasm for this approach to the treatment of aging and age-related disease.

With the additional attention and funding for this field, more methods of selective cell destruction have been established, and there is now a greater and more detailed understanding of the ways in which senescent cells cause harm, contributing to the aging process. Senolytic drugs that induce apoptosis have been discovered; senescent cells are primed to enter the programmed cell death process of apoptosis, and so a small nudge to all cells via a drug treatment kills many senescent cells but very few normal cells. Researchers have established that senescent cells exist in the immune system, and may be important in immune aging. Similarly, the immune cells involved in the progression of atherosclerosis are also senescent, and removing them slows the progression of that condition. Other research has shown that removing senescent cells from the lungs restores lost tissue elasticity and improves lung function. Beyond these specific details, senescent cells clearly contribute to chronic inflammation in aging, and that drives the progression of near all common age-related conditions. The less inflammation the better. These effects are caused by the signals secreted by senescent cells: that their harm is based on signaling explains how a small number of these cells, perhaps 1% by number in an aged organ, can cause such widespread havoc.

2) Immune System Destruction and Restoration

At the present time it is a challenge to pick second place. A number of fields are all equally close to realization, and happenstance in funding decisions, regulatory matters, or technical details yet to be uncovered will make the difference. The destruction and recreation of the immune system wins out because it is already possible, already demonstrated to be successful, and just missing one component part that would enable it to be used by ordinary, healthy, older people. At present researchers and clinicians use chemotherapy to destroy immune cells and the stem cells that create them. Repopulation of the immune system is carried out via cell transplants that are by now a safe and proven application of stem cell medicine, little different from the many varieties of first generation stem cell therapy. This approach has been used to cure people with multiple sclerosis, and has been attempted with varying degrees of success for a number of other autoimmune conditions for going on fifteen years now: there are researchers with a lot of experience in this type of therapy.

The catch here is that chemotherapy is a damaging experience. The cost of undergoing it is high, both immediately, and in terms of negative impact on later health and life expectancy, similar to that resulting from a life spent smoking. It only makes sense for people who are otherwise on their way to an early death or disability, as is the case for multiple sclerosis patients. However, there are a number of approaches very close to practical realization that will make chemotherapy obsolete for the selective destruction of immune cells and stem cells - approaches with minimal or no side-effects. A combined approach targeting c-kit and CD47 was demonstrated earlier this year, for example. Sophisticated cell targeting systems such as the gene therapy approach developed for senescent cell clearance by Oisin Biotechnologies could also be turned to stem cell or immune cell destruction, given suitable markers of cell chemistry. There are quite a few of these, any one of which would be good enough.

Replacing the chemotherapy with a safe, side-effect-free treatment would mean that the established programs for immune system restoration could immediately expand to become a useful, effective treatment for immunosenescence, the age-related failure of the immune system. This is in part a problem of configuration: a lifetime of exposure to persistent pathogens such as herpesviruses leaves too much of the immune system uselessly devoted to specific targets that it cannot effectively clear from the body, and too little left ready to fight new threats and destroy malfunctioning cells. Then there are various forms of autoimmunity that become prevalent in older people, not all of which are in any way fully understood - consider just how recently type 4 diabetes was discovered, for example. Clearing out the entire immune system, all of its memory and quirks, and restarting it fresh with a new supply of stem cells is a good approach to many of the issues in the aged immune system. Not all of them, but many of them, and considering the broad influence immune function has over many other aspects of health and tissue function, it seems a worthwhile goal.

3) Clearance of the First Few Types of Amyloid

There are about twenty different types of amyloid, misfolded proteins that form solid deposits. Not all are robustly associated with age-related dysfunction, but of those that are, some progress has been made towards effective therapies based on clearance. Last year, a clinical trial of transthyretin amyloid clearance produced good results. This type of amyloid is associated with heart disease, and is thought to be the primary cause of death in supercentenarians. This year researchers finally demonstrated clearance of amyloid-β in humans, after a long series of failures. Amyloid-β is one of the forms of metabolic waste that accumulates in Alzheimer's disease.

So these types of rejuvenation therapy already exist in the sense of prototypes and trial treatments. To the degree that they are effective and safe, everyone much over the age of 40 should be undergoing a course of treatment every few years. In practice, since both of the above mentioned therapies are tied up in the slow-moving edifice of Big Pharma regulatory capture, it will be a long time before they make it to the clinic in any way that is accessible to an ordinary individual. The most likely path to that goal is for other groups outside that system to reverse engineer the basic technology from the scientific publications, implement their own methodologies, and market it in other regulatory regions, making it available via medical tourism. This is how stem cell medicine progressed, and seems likely to be the way that any other very significant field will also move forward.

4) Clearance of Glucosepane Cross-Links

Clearance of cross-links in the extracellular matrix of tissues is, like senescent cell destruction, one of the most exciting of early rejuvenation therapies. It is a single target that influences a great many aspects of aging: if we look at just the cross-link-induced loss of elasticity in blood vessels alone, that has a major influence on mortality through hypertension and consequent impact on cardiovascular health. It is also a single target in the sense that near all persistent cross-links important to aging in humans so far appear to be based on one compound, glucosepane. Thus all that is needed is one drug candidate.

Four years ago, the situation for glucosepane clearance looked pretty bleak. The funding was minimal, and the tools for working with glucosepane in living tissues didn't exist. Researchers avoided the whole topic, as making any progress would require a lot of funding and effort to even get to the point of starting in earnest. The SENS Research Foundation and their allies have since made major inroads into this challenge, however. Last year, a method of cheaply and reliably synthesizing glucosepane was established, and now the road is open to anyone who wants to try their hand at drug discovery. That is now underway in the Spiegel Lab, among others, and I'd hope to see the first potential drug candidates emerge at some point in the next couple of years.

5) Thymic Rejuvenation to Increase the Supply of Immune Cells

Another possible approach to partially restore lost function in the aging immune system is to increase the pace at which new immune cells are created. This is a very slow pace indeed in older people, due in large part to the age-related decline of the thymus. The thymus acts as a nursery for the maturation of T cells, and its atrophy thus restricts the rate at which new cells enter circulation. There has been some progress towards engineering of replacement active thymus tissue, as well as methods of providing signal proteins that instruct the old thymus to regenerate and begin to act in a more youthful manner. Transplants of young thymus organs into old mice has demonstrated that this class of approach can produce a meaningful improvement in immune function, and thereby extend healthy life. This is one of a number of regenerative approaches that is on the verge, just waiting for someone to start a company or join the final two dots together and get moving.

6) Mitochondrial Repair

Mitochondria, the power plants of the cell, are herds of bacteria-like organelles that bear their own DNA. This DNA becomes damaged in the course of normal cellular processes, and certain forms of mitochondrial DNA damage - to the thirteen genes needed for oxidative phosphorylation - produce malfunctioning mitochondria that can overtake their cells, either by replicating more readily or being more resistant to quality control mechanisms. Such cells become dysfunctional exporters of harmful signals and oxidized proteins, something that contributes to the progression of atherosclerosis via increased amounts of oxidized lipids in the bloodstream, to pick one example. If we're lucky, a substantial proportion of these cells will become senescent as a result of their mutant mitochondria, and will thus be destroyed by senescent cell clearance therapies. Regardless of whether or not that is true, a method of either repairing or working around this type of damage is needed.

Most of the possible approaches may or may not work well, because of the replication advantage that damaged mitochondria have over normal mitochondria, and are still to be tested in practice rather than theory or demonstration: upregulation of existing repair mechanisms; delivery of extra functional mitochondrial DNA or whole mitochondria; and so forth. The SENS approach is somewhat more radical, involving gene therapy to introduce copies of the thirteen genes into the cell nucleus, altered to ensure that the proteins produced can migrate back to the mitochondria where they are needed. Mitochondria will thus have the necessary protein machinery for correct function regardless of the state of their DNA. This has been demonstrated for three of the thirteen genes of interest, numbers two and three just this year, and getting that far has taken the better part of ten years at a low level of funding. It is likely that things will go faster in the future, now that there is a for-profit company, Gensight Biologics working on the problem in addition to non-profit groups, but it is still the case that the bulk of the work remains to be done.

Will it be useful to have therapies that fix half the problem, moving six or seven genes to the cell nucleus? Will that reduce the impact on aging by half? Hard to say until it is done and demonstrated in mice. Halfway there is probably a target reached by 2020 or so at the present pace. Mitochondrial function appears from all the evidence to be an important aspect of aging, so it is to my eyes worth trying at the halfway point to see what the outcome is.

7) A Robust Cure for Cancer

Some might find it counterintuitive that a universal cure for cancer is not last in this list. We've all been educated to think of cancer as the greatest challenge for medical science, the problem to be solved last of all. Nonetheless, a more rapid arrival of a generally applicable cure for cancer looks to be the likely course of events, as the basis for a treatment that can in principle put a halt to all cancer at all stages of development is currently in the earliest stages of development. All cancers depend absolutely on the ability to continually lengthen telomeres, and so avoid the Hayflick limit on cell replication. Telomere lengthening occurs through the activity of telomerase or the less well understood alternative lengthening of telomeres (ALT) mechanisms: these two are a small set of targets for modern medicine, and researchers are working on the challenge. If telomerase and ALT can both be blocked, temporarily and either globally throughout the body or selectively in cancerous tissue, then cancer will wither and become controllable. This is too fundamental a part of cellular biochemistry for the rapid mutational evolution of cancer cells to work around, as they can for many of the standard approaches to cancer treatment at the present time. Stem cell populations will suffer while telomerase activity is blocked, as they require telomere lengthening for self-renewal, but that is a lesser problem when compared to cancer and one that the stem cell research community will become increasingly able to address in the years ahead.

8) Reversing Stem Cell Aging

The stem cell industry is massively funded, and is on a collision course with stem cell aging. Most of the conditions that one would want to use stem cell therapies to treat are age-related conditions. Researchers must thus ensure that the altered cellular environment, the damage of aging, doesn't prevent the treatments from working - that pristine cells can integrate and work well, not immediately die or decline in response to an age-damaged stem cell niche. On the whole, the research community isn't engaging aggressively with this goal, however. Possible reasons for this include the fact that most stem cell treatments, even without addressing issues of the aged tissue environment, represent a considerable improvement in the scope of what is possible to achieve through modern medicine. So the incentive to go further is perhaps not as strong as it might otherwise be.

Stem cell populations become damaged by age, falling into quiescence or declining in overall numbers. They should be replaced with new populations, but while simple in concept, and even achieved for some cell types, such as the blood stem cells that produce immune cells, this is easier said than done for the body as a whole. Every tissue type is its own special case. There are hundreds of types of cell in the body. Each supporting stem cell population has so far required specific methodologies to be developed, and specific behaviors and biochemistry to be laboriously mapped. It isn't even entirely clear that researchers have found all of the stem cell or stem-like cell populations of interest. There is an enormous amount of work to be done here, and at the moment the field is still largely in the phase of getting the basics, the maps, and the reliable therapeutic methods sorted out for a few of the better understood tissue types, bone marrow and muscles in particular. So this seems at the present time like a long-term prospect, despite the high levels of funding for this line of medical research and development.

9) Clearance of Other Amyloids, Aggregates, and Sundry Lysosomal Garbage

A good portion of aging is driven by the accumulation of waste products, either because they are hard for our biochemistry to break down, is the case for glucosepane cross-links and many of the components of lipofuscin that degrade lysosomal function in long-lived cells, or because clearance systems fail over time, as appears likely to be the case for the amyloid-β involved in Alzheimer's disease. There are a lot of these compounds: a score of amyloids, any number of lipofuscin constituents, the altered tau that shows up in tauopathies, and so on and so forth. In many cases there isn't even a good defensible link between a specific waste compound and specific age-related diseases: the waste is one contribution buried in many contributions, and the research community won't start putting numbers to relative importance until it is possible to clear out these contributions one by one and observe the results.

A range of research groups are picking away at individual forms of waste, some with large amounts of funding, some with very little funding, but this is a similar situation to that I outlined above for stem cell aging. There is a huge amount of work to accomplish because there are many targets to address, and with few exceptions, such as amyloid-β, it is unclear which of the targets are the most important. They will all have to be addressed, in some order, but there are only so many researchers and only so much funding. We can hope that as the first effective therapies make it into the clinic, most likely for the clearance of forms of amyloid, there will be a growing enthusiasm for work on ways to remove other types of metabolic waste.

Some Adaptive Immune Cells Become More Innate-Like in the Aged Immune System
https://www.fightaging.org/archives/2016/11/some-adaptive-immune-cells-become-more-innate-like-in-the-aged-immune-system/

I stumbled upon an interesting open access paper a few days ago, linked below, in which the authors present their view of immunosenescence, the age-related failure of the immune system, as being in part a process wherein some cells of the adaptive immune system change their characteristics and function to become more like innate immune system cells. It makes for interesting reading, though it is worth bearing in mind that the immune system as a whole is fantastically complex, and in many ways still a dark and unmapped forest. It is easy to theorize unopposed when there is such a lot of empty space remaining on the map, making it hard to argue concretely about the relative importance of various mechanisms and observations. This poor understanding of the intricacies of the immune system is why autoimmune diseases and immune aging are largely lacking in effective treatments, and why the best of the prospective cures are those that sidestep the entire question of specific causes and mechanisms in face of the Gordian strategy of destroying the entire immune system in order to start over with new stem cells and immune cells.

As you might know, the immune system of most higher animals is two-layered. The layer that evolved first, and which remains the entirety of the immune system in lower animals such as insects, is known as the innate immune system. It reacts quickly, generates inflammation, and reacts in the same, predictable way to every threat. It has no memory and does not reconfigure its operations in response to circumstances and history. Later in evolutionary history, a second layer known as the adaptive immune system came into being, a more sophisticated set of functions resting on top of the existing innate mechanisms. The innate immune system reacts to intruders, and then the adaptive immune system records the nature of the threat and responds in its own manner, augmenting the attack. As the name suggests, the adaptive immune system maintains a memory and adjusts its operations in order to more aggressively destroy pathogens that it has encountered in the past. As anyone in the field will tell you, however, this high level picture of cleanly divided dualism is overly simplistic, however. There are numerous grey areas and incompletely understood complexities at the border between the two sides of the immune system.

Given that the adaptive immune system can adapt, its failure with aging is in large part a matter of acquired misconfiguration. There is only a small influx of new immune cells in adults, and this puts an effective limit on the number of immune cells that is supported at any one time. The inevitable problem in a space-limited system that keeps a continual record of history is that it runs out of space: evolutionary pressures produced the trade-off of a system that works very well out of the gate in young people, but fails sometime in later life. An old adaptive immune system is burdened with too many cells devoted to memory and too few cells devoted to attacking new threats. That is on top of the progressive failures that occur due to the the growing burden of the molecular damage that accompanies aging: persistent metabolic waste products such as cross-links and lipofuscin, mitochondrial damage, diminished stem cell activity, and so forth. The innate immune system has its own problems that arise from this damage, but is less prone of the issue of misconfiguration.

Understanding exactly how aging progressively harms the intricate choreography of the immune response is a massive project, and nowhere near completion. It is possible to judge how far along researchers are in this work by the side effect of the quality of therapies for autoimmune disease, which are malfunctions in immune configuration, and largely incurable at the present time. From a practical point of view, and as mentioned above, the best prospects for effective treatments in the near future involve destroying and recreating the immune system. That works around our comparative ignorance by removing all of the problems that researchers don't understand in addition to ones that they do. Destroying the immune system can only be done with chemotherapy at the moment, which no-one would undergo unless there was no choice in the matter given that it has significant negative effects on long-term health, but once new methods of selective immune cell destruction are developed, lacking side-effects, then we can start to talk about treating immune aging by rebooting the immune system.

Convergence of Innate and Adaptive Immunity during Human Aging

Aging is associated with a general decline in immune function, contributing to a higher risk of infection, cancer, and autoimmune diseases in the elderly. Such faulty immune responses are the result of a profound remodeling of the immune system that occurs with age, generally termed as immunosenescence. While the number of naïve T cells emerging from the thymus progressively decreases with age as a result of thymic involution, the memory T cell pool expands and exhibits significant changes in the phenotype and function of antigen-experienced T cells, particularly evident in the CD8+ T cell compartment. Chronic immune activation due to persistent viral infections, such as cytomegalovirus (CMV) and Epstein-Barr virus (EBV), is one of the main drivers contributing to the accumulation of highly differentiated antigen-specific CD8+ T lymphocytes that have characteristics of replicative senescence. In combination with the depletion of the peripheral pool of naïve T cells, the accumulation of these terminally differentiated T cells with age skews the immune repertoire and has been implicated in the impaired immune responses to new antigens and vaccination in the elderly

Natural killer cells and αβCD8+ T lymphocytes are the two major cell lineages with constitutive cytotoxic activity and have a crucial role in the recognition and killing of abnormal cells. However, the paradigm for the recognition of target cells is fundamentally different between these two cell types: conventional αβCD8+ T cells rely on the T cell receptor (TCR) to recognize specific peptides presented by major histocompatibility complex class-I (MHC-I) molecules, whereas NK cells use a repertoire of germ line-encoded receptors to detect "missing self" or "altered-self" antigens and directly kill abnormal cells, without prior sensitization. Besides antigen specificity, the development of immunological memory is conventionally another distinctive feature between NK and T cells, categorizing them into distinct arms of the immune system and the innate and adaptive immune system, respectively.

Nevertheless, accumulating evidence supports the existence of NK cell memory, as well as evidence for TCR-independent responses mediated by αβCD8+ T lymphocytes, suggesting that the conventional limits between the innate and adaptive arms of the immune system may be not as distinct as first thought. NK and T lymphocytes have a common origin from a lymphoid progenitor cell in the bone marrow, and recent comparative proteomic and transcriptomic studies have demonstrated a remarkably close proximity between effector αβCD8+ T lymphocytes and NK cells, reiterating an evolutionary ancestry and shared biology between the two cell lineages.

An increasing body of literature reveals the existence of subsets of T cells with features that bridge innate and adaptive immunity. These cells typically co-express a TCR and NK cell lineage markers, distinguishing them from NK cells and other innate lymphoid cells, which lack the expression of a TCR or somatically rearranged receptors. Functionally, innate-like T cells respond to TCR ligation but are also able to respond rapidly to danger signals and pro-inflammatory cytokines, independently of TCR stimulation, resembling innate cells. Recently, subsets of conventional αβCD8+ T cells expressing NK cell markers and intraepithelial T cells have been included in this vaguely defined group of innate-like T cells. Despite the similarities in phenotype and function, there are clear differences in ontogeny and tissue distribution between them.

In this review, we will discuss recent evidence that aging is associated with the expansion of a subset of conventional αβCD8+ T cells with phenotypic, functional, and transcriptomic features that resemble NK cells. Such innate-like αβCD8+ T cells have the characteristics of terminally differentiated T cells, and the acquisition of functional NK receptors is most likely part of a general reprograming of the CD8+ T cell compartment during human aging, to ensure broad and rapid effector functions. We propose that innate-like αβCD8+ T cells share important features with other innate-like T cells; however, fundamental differences in origin and development separate them from truly innate cells. Interestingly, these cells are also differentially affected by aging, suggesting distinct roles in immune responses at different times of life. Evidence indicates that chronological aging is associated with accumulation of cells combining features of both the innate and adaptive arms of the immune system, most likely to compensate for functional defects of conventional NK and CD8+ T cells with age. We propose that senescent CD8+ T cells should not be seen as a dysfunctional population but instead a functionally distinct subset, which uses recently acquired NK cell machinery to maintain rapid effector functions throughout life. Contrary to the classic paradigm that peripheral TCR ligation is essential for T cell activation, this subset of highly differentiated T cells has impaired TCR responsiveness and may be non-specifically activated by inflammatory cytokines or after ligation of innate receptors. The switch to an innate mode of function may shed light on the mechanisms that allow highly differentiated CD8+ T cells to maintain functionality, despite the loss of TCR signal functions.

Our understanding of the physiological significance of the expression of NKRs on T cells is still incomplete, and the identification of the molecular mechanisms and the transcriptional regulators underpinning the development of innate features in T cells is essential. Most importantly, it will be important to understand how the intersection between innate and adaptive immune features may be manipulated to enhance immune function and to use this information to develop new approaches to improve immunity in the elderly.

Linking Excess Fat Tissue, Immune Dysfunction, and Cellular Senescence in Aging
https://www.fightaging.org/archives/2016/11/linking-excess-fat-tissue-immune-dysfunction-and-cellular-senescence-in-aging/

Cellular senescence is one of the root causes of aging, and there are at present serious, well-funded efforts underway to produce rejuvenation therapies based on the selective destruction of senescent cells in old tissues. This progress is welcome, but it could have started a long time ago. It has taken many years of advocacy and the shoestring production of technology demonstrations to finally convince the broader community of scientists and funding institutions that the evidence has long merited serious investment in treatments to clear senescent cells. This is what it is, and now we must look to the future, for all that it has been a long, uphill battle. Cellular senescence is today having its time in the sun. Many research groups are linking the mechanisms of senescence to other aspects of aging; senescent cells are showing up in many more research papers than in past years, now that there is more of a scientific and financial incentive to search carefully for their influence. I think that declaring cellular senescence to be the causal nexus of aging, as one research group did, is going overboard a little, as there are, after all, other independent causes of aging, forms of metabolic waste and damage that would cause death and disease even if cellular senescence did not exist. Nonetheless, it is gratify to watch the spreading realization that cellular senescence plays a role in many areas of health and biology associated with aging. The advent of therapies that can remove senescent cells promises to produce sweeping beneficial effects on aging and disease.

There is a set of fairly well established threads of research that link aging with visceral fat tissue and immune dysfunction in the form of chronic inflammation. Visceral fat produces an accelerated pace of aging by generating greater chronic inflammation, producing an hostile tissue environment of inappropriate signals that attract immune cells and then cause those cells to become dysfunctional. The more fat there is the more inflammation it creates. This is thought to be the primary mechanism by which obesity increases the risk and severity of age-related disease. All of the common age-related diseases are accelerated in their progression by higher levels of chronic inflammation. The material difference between a lot of fat and a normal amount of fat is well demonstrated by a study in which researchers produced life extension in mice through surgical removal of visceral fat, but there is a mountain of data on human health to show that people who are overweight will suffer a shorter life expectancy and more age-related illness, and that this effect scales by the amount of excess fat tissue. How do senescent cells fit into this picture? One of the characteristic features of senescent cells is that they produce greater levels of chronic inflammation via the secretion of signal molecules such as cytokines. Of late, researchers have shown that senescent cells are found in the immune system, as in other cell populations. Given this, it should not be a surprise to find that cellular senescence can be implicated in the way in which visceral fat accelerates aging: their presence in visceral fat tissue and the immune cells interacting with that tissue fits right in with the broader picture of inflammation and bad cellular behavior.

Obesity accelerates T cell senescence in murine visceral adipose tissue

Visceral obesity is associated with chronic low-grade inflammation in visceral adipose tissue (VAT) and a sustained whole-body proinflammatory state, which may underlie metabolic and cardiovascular diseases. VAT inflammation associated with obesity involves a complex network of responses of immune cell components, including acquired immune cells such as various subsets of T cells and B cells and innate immune cells such as macrophages. Among these cells, CD4+ T cells have been recognized as a central regulator of chronic VAT inflammation. The number of CD4+ T cells in VAT increases as the tissue expands in obesity. Factors that drive CD4+ T cell expansion and into proinflammatory effectors in VAT during the development of high-fat diet-induced (HFD-induced) obesity may include MHC class II-associated antigens, possibly self-peptides, because the T cell receptor (TCR) repertoire of CD4+ T cells in VAT is limited, and deficiency of MHC class II protects mice from high fat diet (HFD)-induced VAT inflammation and insulin resistance. However, the obesity-associated immune background underlying chronic inflammation in VAT remains elusive.

Significant changes occur in the overall T cell populations with age. In CD4+ T cells, proportions of naive (CD44loCD62Lhi) cells sharply decline in ontogeny, with an age-dependent increase in cells of the memory phenotype (CD44hiCD62Llo). Among CD44hiCD4+ T cells, a unique population expressing programmed cell death 1 (PD-1) and CD153 actually increases with age in mice. The CD153+PD-1+CD44hiCD4+ T cell population shows compromised proliferation and regular T cell cytokine production on T cell receptor (TCR) stimulation but secretes large amounts of proinflammatory cytokines, such as osteopontin. These CD4+ T cells also show signatures of cell senescence, including a marked increase in senescence-related gene expression and nuclear heterochromatin foci, and are termed senescence-associated T cells (SA-T cells). Notably, the age-dependent development of SA-T cells, which may include autoreactive cells, is dependent on B cells. As such, the increase in SA-T cells is suggested to be involved in part in immune aging phenotypes such as impaired acquired immune capacity, increased proinflammatory traits, and high risk for autoimmunity.

In the present study, we demonstrate that CD153+PD-1+CD44hiCD4+ T cells are remarkably increased and preferentially accumulated in the VAT of HFD-fed mice in a B cell-dependent manner and that these CD4+ T cells show functional and genetic features strongly resembling SA-T cells that increase in secondary lymphoid tissues with age. We also indicate that the CD153+PD-1+CD44hiCD4+ T cells play a crucial role in inducing chronic VAT inflammation and metabolic disorder via secretion of large amounts of osteopontin. We demonstrated that adoptive transfer of CD153+PD-1+CD44hiCD4+ T cells, but not other CD4+ T cells, from HFD-fed spleens into VAT of ND-fed mice recapitulates the features of VAT inflammation, including a striking increase in CD11chiCD206lo macrophages and expression of proinflammatory cytokine genes. It is noteworthy that CD153+PD-1+CD4+ T cells in VAT of HFD-fed mice show features indistinguishable from those of CD153+ SA-T cells, which gradually increase systemically with age. The age-dependent increase in CD153+ SA-T cells may partly underlie the immune aging, including a reduction in acquired immunity and an increase in the inflammatory trait and autoimmunity risk. Obesity is also associated with diminished resistance against infection, chronic low-grade inflammation, and a greater susceptibility to autoimmunity. It has been suggested that the increase in CD153+ SA-T cells in chronological aging and systemic autoimmunity is attributable to a robust, homeostatic T cell proliferation, but the precise mechanism underlying the accumulation of these T cells in VAT of HFD-fed mice remains to be investigated. Nonetheless, it is an intriguing possibility that the predisposition often associated with obesity may partly be a systemic manifestation of the premature increase in CD153+ SA-T cells in VAT, since adipose tissues can constitute up to 50% to 60% of total BW in severe obesity.

Latest Headlines from Fight Aging!

A Look at Scaling Up the Tissue Engineering of Larger Blood Vessels
https://www.fightaging.org/archives/2016/11/a-look-at-scaling-up-the-tissue-engineering-of-larger-blood-vessels/

Perhaps the greatest challenge in the field of tissue engineering is the production of integrated networks of small blood vessels sufficient to support larger tissue sections. Without a reliable way to do this, researchers are limited to producing the tiny functional tissue masses known as organoids. When it comes to making larger blood vessels, however, good progress is being made. This article takes a look at the efforts of one alliance of research groups, aiming for the widespread, cost-effective availability of engineered arteries:

The prospect of creating artery "banks" available for cardiovascular surgery, bypassing the need to harvest vessels from the patient, could transform treatment of many common heart and vascular ailments. But it's a big leap from concept to reality. Patients needing bypass surgeries would benefit from a better source for arteries. Replacement tissue currently comes from another part of the patient's body, and suitable tissue can't be found for many patients. Current synthetic alternatives also fail at a high rate. Diseases of blood vessels - including coronary artery disease - kill more people worldwide than any other single cause.

"Tissue engineering for blood vessels is a pretty mature field. But there are still two major problems: One is the time it takes to make the vessels, and the other is the source of the cells to grow them." For example, taking induced pluripotent (iPS) stem cells from an individual patient, growing the relevant cells and assembling them into an artery would overcome the problem of transplant rejection. However, it would be cost-prohibitive and take months to complete - too long to be clinically useful to a patient. The promising alternative is to create tissue with cells banked from a unique population of people who are genetically compatible donors, based on rare alleles that circumvent rejection. It has been estimated that about 100 different cell lines from this rare population would be enough to cover a majority of the U.S. population.

A new effort covers four phases and addresses key questions about the feasibility of this approach. The model for the project is designed around treating critical limb ischemia, a debilitating condition that restricts blood flow to limbs and often leads to amputation or death. Researchers are working to create the optimal cellular building blocks of the artery - endothelial and smooth muscle cells - that will be most suitable for transplantation and continue to grow and remodel in the patient. In tandem, a different team will develop scaffolds from natural and synthetic materials to provide structure and shape for the artery. Other researchers will build a bioreactor that provides an environment in which the arterial cells can grow around the scaffolding. The transplant surgery and resulting immune response will then be tested using a monkey limb ischemia model. Having a primate model is important to produce results more relevant to human health than those from mice or other short-lived animals. Finally, there is the production of arterial cells that meet FDA standards for human clinical trials, paving the way for potential treatments for limb ischemia in humans. If the entire process works, researchers estimate that potential human therapies remain about 10 years away.

Mitochondrial Antioxidant SkQ1 as a Treatment for Age-Related Dry Eye Syndrome
https://www.fightaging.org/archives/2016/11/mitochondrial-antioxidant-skq1-as-a-treatment-for-age-related-dry-eye-syndrome/

The mitochondrially targeted antioxidant SkQ1 and other compounds in its family have moved into commercial development in Europe. Over the past decade these plastoquinone derivatives have been shown to modestly slow aging in flies and mice, but the greatest and most reliable effects involve reduction of inflammation and effective treatment of inflammatory eye conditions. Thus clinical development has focused on diseases such as dry eye syndrome, an unpleasant condition caused by age-related dysfunction of the lacrimal gland responsible for tear secretion. Aging eventually causes problems in every bodily system, including those that we tend to take for granted, not realizing that we will be greatly pained and inconvenienced by their failure.

Dry eye syndrome (DES) is a frequent eye disorder affecting many people worldwide, especially at an old age. DES is a multifactorial disorder of the ocular surface unit and results in eye discomfort, visual disturbances, and tear film instability with potential damage to the ocular surface and often poor quality of life. Current therapies for DES are only palliative, focusing on replacement of tear fluid to reduce the symptoms. Thus, there is a need for drugs that directly address the causes of DES. Clinical and basic studies have shown that the age-related decline of lacrimal-gland functions decreases the ability to synthesize and secrete proteins. These alterations may cause aqueous tear deficiency in DES. Approximately 80% of the lacrimal gland is acinar cells: highly differentiated epithelial cells specialized for the synthesis, storage, and secretion of tear fluid components, such as water, proteins, glycoproteins, and electrolytes. During aging, the synthesis and secretion of proteins decrease in lacrimal glands, and acinar cells start to produce and secrete a mucous product. The latter causes aberrations in the tear film of the eyes.

Researchers have compared ultrastructure of mitochondria in acinar cells of 6- and 12-month-old ad libitum fed Fischer 344 rats and uncovered occasional mitochondrial swelling, disorientation, shortening, and disorganization of cristae in the 12-month-old animals. Mitochondria, when dysregulated, are a major source and target of oxidative stress. Mitochondrial dysfunction strongly promotes aging and the pathogenesis of age-related diseases including eye diseases. Some authors demonstrated a connection of age-related alterations in the lacrimal gland with oxidative stress. Other authors showed the possibility of interventions (e.g., calorie restriction) aimed at reducing excessive production of reactive oxygen species (ROS) to prevent disturbances in the mitochondrial ultrastructure of acinar cells in the lacrimal gland. Changes in signaling pathways associated with age-related upregulation of oxidative stress have been detected in the aging lacrimal gland. Increased oxidative stress can result from reductions in insulin secretion and parasympathetic signaling accompanied by an increase in hormone resistance and by accumulation of advanced glycation end products in the aging lacrimal gland.

Thus, an increasing body of evidence suggests that prevention of upregulation of mitochondrial ROS is important for possible therapeutic strategies to delay age-associated alterations and to prevent age-related disorders in humans. Despite the disappointing effects of antioxidants in clinical trials, there is growing evidence of beneficial effects of mitochondria-targeted antioxidants during aging and in age-related diseases. Previously, we showed that mitochondria-targeted antioxidant 10-(6′-plastoquinonyl) decyltriphenyl phosphonium cation (SkQ1) ameliorates the signs of aging and inhibits the development of such age-related diseases as cataract, age-related macular degeneration, and glaucoma in rats. SkQ1 (under the brand name Visomitin) in the form of eye drops is already manufactured and has been successfully used since 2012 for treatment of DES in Russia. Nevertheless, the link between SkQ1's effects and its suppression of age-related aberrations in the lacrimal gland has not been explored. The aim of this study was to examine the effects of long-term dietary supplementation with SkQ1 on age-related deterioration of lacrimal-gland ultrastructure Wistar rats.

Here we demonstrated that dietary supplementation with SkQ1 (250 nmol/[kg body weight] daily) starting at age 1.5 months significantly alleviated the pathological changes in lacrimal glands of Wistar rats by age 24 months. By this age, lacrimal glands underwent dramatic deterioration of the ultrastructure that was indicative of irreversible disturbances in these glands' functioning. In contrast, in SkQ1-treated rats, the ultrastructure of the lacrimal gland was similar to that in much younger rats. Morphometric analysis of electron-microscopic specimens of lacrimal glands revealed the presence of numerous secretory granules in acinar cells and a significant increase in the number of operating intercalary ducts. Our results confirm that dietary supplementation with SkQ1 is a promising approach to healthy ageing and to prevention of aberrations in the lacrimal gland that underlie dry eye syndrome.

Manipulating Existing Methods of Cellular Quality Control to Clear Mutant Mitochondria
https://www.fightaging.org/archives/2016/11/manipulating-existing-methods-of-cellular-quality-control-to-clear-mutant-mitochondria/

The SENS view of mitochondrial damage in aging starts with the fact that deletions accrue to mitochondrial DNA. When those deletions remove one or more of the thirteen genes necessary to the primary processes of energy generation, the mutant becomes either more able to replicate or more able to resist destruction by quality control processes. In some cases, the mutant strain takes over the cell and turns it into a dysfunctional exporter of harmful, reactive molecules. There are even mechanisms by which such broken mitochondria can be exported to surrounding cells, spreading the rot. We accumulate a small but significant population of these malfunctioning cells over the years, and this is one of the root causes of aging and age-related disease. It is a step on the way to the production of oxidized lipids, to pick one example of the downstream consequences, and that contributes to the progression of atherosclerosis.

The SENS approach to remediation involves gene therapy to produce backup copies of the necessary mitochondrial genes, ensuring that the supply of vital protein machinery isn't interrupted by genetic damage in mitochondria. Is it possible, however, to manipulate the existing machinery of mitochondrial quality control to ensure that mutants are reliably destroyed rather than slipping past the net? This is an open question, and good arguments can be made either way: one the one hand, the existing system is pretty comprehensive but still fails catastrophically, allowing mutant mitochondria to very quickly overtake their cells. It isn't clear that simply dialing up quality control activity is going to help at all. On the other hand, cells that are reprogrammed for pluripotency quite clearly rejuvenate their mitochondria. Answering this question is better achieved through action rather than debate: in this open access paper researchers demonstrate clearance of mutant mitochondria with large deletions from fly tissues via manipulation of existing quality control systems as a proof of principle. It isn't at all clear to me from reading the paper that the authors have created a mutant strain that deletes the important genes relevant to aging, however, and therein lies the vital detail. They have, however, created the basis for model organisms that could be used for further exploration of this topic, in a more efficient manner than has been possible in the past.

Mitochondria are membrane-bound organelles present in many copies in most eukaryotic cells. The circular mitochondrial genome (mtDNA) encodes proteins necessary for oxidative phosphorylation, which generates the bulk of ATP in most cells. Individual mitochondria contain multiple copies of mtDNA, each of which is packaged into a structure known as a nucleoid, with primarily a single mtDNA per nucleoid. This multiplicity of genomes per cell, in conjunction with mtDNA's high mutation rate and limited repair capacity, often results in cells carrying mtDNA of different genotypes, a condition known as heteroplasmy. Recent studies suggest that 90% of individuals have some level of heteroplasmy, with 20% harbouring heteroplasmies that are implicated in disease. If the frequency of such a mutation reaches a threshold, pathology results. Heteroplasmy for deleterious mtDNA can also arise in somatic tissues during development and in adulthood. It accumulates throughout life, and is thought to contribute to diseases of aging. These observations emphasize the importance of devising ways to reduce heteroplasmy in vivo.

Mitochondria-targeted site-specific nucleases provide one way to decrease the levels of heteroplasmy. In this approach, a site-specific nuclease is engineered so as to bind and cleave a specific mutant version of the mtDNA genome, promoting its selective degradation. This approach has recently been used to decrease the levels of heteroplasmy in patient-derived cell lines, in oocytes and in single cell embryos. However, these methods are likely to be challenging to implement in the adult, as the nuclease being expressed is a non-self protein; many cells must be targeted without off target cleavage effects; and individuals may be heteroplasmic for multiple deleterious mutations. Here we seek to promote cell biological processes that normally regulate mtDNA quality as an alternative approach to decreasing heteroplasmy in adults.

Mitophagy serves as a form of quality control that promotes the selective removal of damaged mitochondria. In one important pathway, dysfunctional mitochondria are eliminated through a process dependent on PTEN-induced putative kinase 1 (PINK1) and Parkin, loss of which lead to familial forms of Parkinson's disease. Regardless, the fact that mutant mtDNA accumulates in individuals wild type for PINK1 and parkin during aging indicates that if PINK1- and Parkin-dependent mitophagy and/or other pathways promote mtDNA quality control, they are often not active or effective. To identify ways of reducing the mutant mtDNA load in somatic tissues, systems are needed in which a specific deleterious heteroplasmy can be induced in vivo and followed over time, ideally in post-mitotic cells so as to eliminate potential confounding effects associated with stochastic segregation during cell division, and differential cell proliferation and/or cell death. Current in vivo models are cumbersome and limited, but we describe the generation and use of a transgene-based system of heteroplasmy in post-mitotic muscle to identify conditions that result in the selective removal of mutant mtDNA.

We demonstrate that the load of deleterious mtDNA can be decreased through several different interventions. Genetic and chemical screens using such a model should prove useful in identifying molecules that can cleanse tissues of a deleterious genome, via known and unknown mitochondrial quality control pathways. The many tools for regulated spatial and temporal control of gene expression in Drosophila will allow such screens to be carried out in a variety of tissues and environmental contexts, including aging. Our results show that adult muscle has a significant but limited ability to remove mutant mtDNA utilizing genes required for autophagy, and that mutant mtDNA removal can be greatly stimulated in several ways: by limiting the ability of mitochondrial fragments to re-fuse with the network (decreasing Mfn levels), by limiting their ability to undergo repolarization through ATP synthase reversal (ATPIF1 expression), by increasing the tagging of mtDNA-bearing fragments (increasing PINK1 or Parkin levels), and by increasing the frequency with which these tagged fragments are degraded (activation of autophagy). These observations have important implications for new therapies for mitochondrial disease and diseases of aging.

Dementia Risk is Declining, for Reasons Yet to be Conclusively Established
https://www.fightaging.org/archives/2016/11/dementia-risk-is-declining-for-reasons-yet-to-be-conclusively-established/

The risk of suffering dementia has fallen in recent years. The researchers involved in the paper here are reporting on epidemiological data, so the underlying reasons for this decline remain to be established conclusively. If I had to guess, it would be the increasing focus on control of blood pressure and other preventative cardiovascular treatment in medical practice. Dementia is driven in large part by the age-related failures of the vascular system. Stiffening of blood vessels leads to hypertension, which in turn damages sensitive tissues either through nothing more than greater pressure, or through greater rates of structural failure in small blood vessels, killing tissue one tiny volume at a time. There are other, less immediately physical mechanisms by which higher blood pressure degrades the normal operation of the brain as well, such as disruption of immune cell behavior. So it is entirely plausible to think that the approaches that have successfully reduced the risk of cardiovascular disease over the past few decades are also having an impact on dementia. Interestingly, the data in the paper suggests that the more recent improvements are not due to that cause, but you always have to weigh the details of any one paper against the bigger picture that emerges from all recent work on the topic.

Dementia, a decline in memory and other cognitive functions that leads to a loss of independent function, is a common and feared geriatric syndrome that affects an estimated 4 to 5 million older adults in the United States and has a large social and economic impact on patients, families, and government programs. Although the number of older adults with dementia in the United States and around the world is expected to grow up to 3-fold by 2050 owing to the large increase in the size of the elderly population, recent studies suggest that the age-specific risk of dementia may have actually declined in some high-income countries over the past 25 years, perhaps owing to increasing levels of education and better control of key cardiovascular risk factors, such as hypertension, diabetes, and hypercholesterolemia. For instance, the incidence of dementia among older participants in the Framingham Heart Study declined by about 20% per decade between 1977 and 2008, and the decline in risk was seen only among those with at least a high school education. If confirmed in representative populations, a decline in age-specific risk for dementia would have important implications for public health and public policy. For instance, a recent population-based study of dementia in England found a 24% decline in the expected number of cases of dementia between 1991 and 2011 (a 6.5% prevalence among older adults in 2011, compared with 8.3% in 1991), which translates to more than 200,000 fewer cases of dementia.

There have been changes over the past 2 to 3 decades in both the prevalence and treatment of cardiovascular risk factors that also influence the risk for dementia. For instance, 23% of US adults were obese in 1990 compared with 35% in 2012; among adults 65 years or older, the prevalence of diabetes increased from 9% to 21%. However, intensity of treatment for diabetes, hypertension, and high cholesterol level has increased with more patients achieving treatment goals, and a significant decline in the vascular complications of diabetes such as heart attack, stroke, and lower-extremity amputations, suggesting that there could be a "spill-over" benefit of a decline in the vascular-related risk for dementia. Rising levels of education among US adults over the past 25 years may also have contributed to decreased dementia risk. The proportion of adults 65 years or older with a high school diploma increased from 55% in 1990 to 80% in 2010, while the proportion with a college degree increased from 12% to 23%. More years of formal education is associated with a reduced risk of dementia, likely through multiple causal pathways, including a direct effect on brain development and function (i.e., the building of "cognitive reserve"), health behaviors, as well as the general health advantages of having more wealth and opportunities.

In a large nationally representative survey of older Americans we found that, among those 65 years or older, the prevalence of dementia decreased from 11.6% to 8.8% between 2000 and 2012, representing an absolute decrease of 2.8 percentage points, and a relative decrease of about 24%. Educational attainment increased significantly, with those 65 years or older in 2012 having nearly 1 additional year of education compared with the 2000 cohort. After controlling for the socioeconomic factors of education, wealth, and race/ethnicity, controlling for changes in the prevalence of cardiovascular risk factors did not explain much of the additional difference in dementia risk across the two cohorts. Our findings are consistent with those of a number of recent studies that also found declines in dementia incidence or prevalence in high-income countries around the world and also suggest that the trend toward a declining prevalence of cognitive impairment or dementia in the United States that we found between 1993 and 2002 using earlier data has continued through 2012, even with significant increases in the prevalence of cardiovascular risk factors that may increase dementia risk.

Evidence to Suggest Parabiosis Effects Result from Dilution of Damage
https://www.fightaging.org/archives/2016/11/evidence-to-suggest-parabiosis-effects-result-from-dilution-of-damage/

Heterochronic parabiosis involves joining the circulatory systems of an old and a young mouse. This produces harmful effects on the young mouse and beneficial effects on the old mouse. There is considerable interest in the research community in identifying the molecular signals involved. So far theory has focused on delivery of beneficial signals from young blood to the old individual, but here researchers present evidence to suggest it may be more a matter of diluting detrimental signals present in the old blood. This has implications for efforts to build therapies based on transfusions of young blood: if dilution is the primary mechanism, those efforts will have little to no effect.

A new study found that tissue health and repair dramatically decline in young mice when half of their blood is replaced with blood from old mice. The study argues against the rejuvenating properties of young blood and points to old blood, or molecules within, as driving the aging process. "Our study suggests that young blood by itself will not work as effective medicine. It's more accurate to say that there are inhibitors in old blood that we need to target to reverse aging." In 2005, researchers found evidence for tissue rejuvenation in older mice when they are surgically joined to younger mice so that blood is exchanged between the two. Despite remaining questions about the mechanism underlying this rejuvenation, media coverage of the study fixated on the potential of young blood to reverse the aging process, and on comparisons to vampires, which was not the takeaway from the study. In the years since the 2005 study, scientists have spent millions to investigate the potential medical properties of youthful blood with enterprises emerging to infuse old people with young blood. "What we showed in 2005 was evidence that aging is reversible and is not set in stone. Under no circumstances were we saying that infusions of young blood into elderly is medicine."

While the experimental model used in the 2005 study found evidence that some aspects of aging may be reversed, the techniques used in the study do not allow scientists to precisely control the exchange of blood, which is necessary to dig deeper into blood's effect on aging. When two mice are sutured together, a technique called parabiosis, blood is not the only thing that is exchanged in this setup; organs are also shared, so old mice get access to younger lungs, thymus-immune system, heart, liver and kidneys. In surgical suturing it takes weeks to a month for the effects of blood to take place and the precise timing is not actually known. Nor is the precise amount of the exchanged blood. In the new study, researchers developed an experimental technique to exchange blood between mice without joining them so that scientists can control blood circulation and conduct precise measurements on how old mice respond to young blood, and vice versa. In the new system, mice are connected and disconnected at will, removing the influence of shared organs or of any adaptation to being joined. One of the more surprising discoveries of this study was the very quick onset of the effects of blood on the health and repair of multiple tissues, including muscle, liver and brain. The effects were seen around 24 hours after exchange.

With the new experimental setup, the research team repeated the experiments from 2005. In each test, blood was exchanged between an old mouse and a young mouse until each mouse had half its blood from the other. The researchers then tested various indicators of aging in each mouse, such as liver cell growth as well as liver fibrosis and adiposity (fat), brain cell development in the region that is needed for learning and memory, muscle strength and muscle tissue repair. In many of these experiments, older mice that received younger blood saw either slight or no significant improvements compared to old mice with old blood. Young mice that received older blood, however, saw large declines in most of these tissues or organs. The most telling data was found when researchers tested blood's impact on new neuron production in the area of the brain where memory and learning are formed. In these experiments, older mice showed no significant improvement in brain neuron stem cells after receiving younger blood, but younger mice that received older blood saw a more than twofold drop in brain cell development compared to normal young mice. The researchers think that many benefits seen in old mice after receiving young blood might be due to the young blood diluting the concentration of inhibitors in the old blood.

Zebrafish Extracellular Matrix Produces Enhanced Regeneration in Mouse Hearts
https://www.fightaging.org/archives/2016/11/zebrafish-extracellular-matrix-produces-enhanced-regeneration-in-mouse-hearts/

The big question in the study of the comparative biology of regeneration is the degree to which mammals retain the mechanisms needed for the exceptional regeneration found in species such as zebrafish and salamanders. The individuals of these highly regenerative species are capable of regrowing fins, limbs, and major portions of internal organs. Has evolution removed this machinery from mammals, or only buried it, leaving it dormant and awaiting activation? This experiment, in which the molecular signals provided via transplanted extracellular matrix material from zebrafish are shown to enhance heart regeneration in mice, argues for the latter theory. The heart in mammals is among the least regenerative of tissues, and does not recover well from damage, but there is considerable room for improvement in the healing processes for all mammalian tissues. Zebrafish and other highly regenerative species heal without scars and without loss of function, something that cannot be said for mammals.

Many lower forms of life on earth exhibit an extraordinary ability to regenerate tissue, limbs, and even organs - a skill that is lost among humans and other mammals. Now, researchers have used the components of the cellular "scaffolding" of a zebrafish to regenerate heart tissues in mammals, specifically mice, as well as exhibiting promising results in human heart cells in vitro. The researchers found that a single administration of extracellular matrix (ECM) material from zebrafish hearts restored the function of the heart and regenerated adult mouse heart tissues after acute myocardial infarction. The study also found that the zebrafish ECM protected human cardiac myocytes - specialized cells that form heart muscle - from stresses.

ECM are the architectural foundations of tissues and organs; not only do they provide a "scaffolding" on which cells can grow and migrate, they assist in the signaling necessary for the organ to develop, grow, or regenerate. In mammals, the heart quickly loses the ability to regenerate after the organism is born, except for a brief period after birth. In lower animals, such as zebrafish, the heart retains that ability throughout their lives: up to 20 percent of a zebrafish's heart can be damaged or removed, and within days the heart's capacity has been fully restored. The researchers first separated the ECM from the cells so that the recipient heart would not reject the treatment. They did this by freezing the zebrafish cardiac tissue, causing the cell membranes to burst and allowing the researchers to retrieve the ECM, a process called decellularization. They then injected the ECM into the hearts of mice with damaged heart muscles and watched the hearts repair themselves. It is difficult to inject foreign cells into a body because the body will recognize them as foreign and reject them. That's not the case with ECM because it is composed of collagen, elastin, carbohydrates and signaling molecules and has no cell surface markers, DNA or RNA from the donor, and so the recipient is less likely to reject the treatment.

Restored function starts almost immediately, and healing is noticeable as early as five days after treatment; within a week, his team could see the heart beating more strongly than the hearts of the untreated animals. The researchers tested the effectiveness of ECM from normal zebrafish and from zebrafish with damaged hearts, in which the ECM had already begun the healing process. They found that while both types of ECM were effective in repairing damage to the mice hearts, the ECM obtained from the zebrafish hearts that were healing were even more potent in restoring heart function in the mice. The researchers are now working on a process to regenerate nerves in mammals using the same process and hope to expand the heart treatments to larger animals in a future study.

Growing Intestinal Tissue Organoids with Functional Nerves
https://www.fightaging.org/archives/2016/11/growing-intestinal-tissue-organoids-with-functional-nerves/

In the field of tissue engineering, this is the era of organoids. Researchers are limited in the size of tissue they can produce because of the lack of a robust method of generating the blood vessel networks needed to support large tissue sections, but are otherwise making significant progress in the generation of functional organ tissue. Initially this is producing the greatest benefit for further research and development, allowing tests to be conducted in living tissue at a much faster pace and lower cost. For many tissue types, however, organoids also offer the possibility of benefits realized through transplantation, as in many cases they are capable of integrating with existing organ tissue to improve its function.

Scientists report using human pluripotent stem cells to grow human intestinal tissues that have functioning nerves in a laboratory. The paper puts medical science a step closer to using human pluripotent stem cells (which can become any cell type in the body) for regenerative medicine and growing patient-specific human intestine for transplant. "One day this technology will allow us to grow a section of healthy intestine for transplant into a patient, but the ability to use it now to test and ask countless new questions will help human health to the greatest extent." This ability starts with being able to model and study intestinal disorders in functioning, three-dimensional human organ tissue with genetically-specific patient cells. The technology will also allow researchers to test new therapeutics in functioning lab-engineered human intestine before clinical trials in patients.

Researchers started out by subjecting human pluripotent stem cells to a biochemical bath that triggers their formation into human intestinal tissue in a petri dish. The process was essentially the same as that used in a 2010 study, which reported the first-ever generation of three-dimensional human intestinal organoids in a laboratory. Intestinal tissues from the initial study lacked an enteric nervous system, which is critical to the movement of waste through the digestive tract and the absorption of nutrients. The gastrointestinal tract contains the second largest number of nerves in the human body. When these nerves fail to work properly it hinders the contraction of intestinal muscles. To engineer a nervous system for the intestinal organoids already growing in one petri dish, researchers generated embryonic-stage nerve cells called neural crest cells in a separate dish. The neural crest cells were manipulated to form precursor cells for enteric nerves. The challenge at this stage was identifying how and when to incorporate the neural crest cells into the developing intestine. "We tried a few different approaches largely based on the hypothesis that, if you put the right cells together at the right time in the petri dish, they'll know what do to. It was a long shot, but it worked." The appropriate mix caused enteric nerve precursor cells and intestines to grow together in a manner resembling developing fetal intestine.

A key test for the engineered intestines and nerves was transplanting them into a living organism - in this case laboratory mice with suppressed immune systems. This allowed researchers to see how well the tissues grow and function. Study data show the tissues work and are structured in a manner remarkably similar to natural human intestine. They grow robustly, process nutrients and demonstrate peristalsis - series of wave-like muscle contractions that in the body move food through the digestive tract.

The Gender Longevity Gap is Consistent Over Populations and Time
https://www.fightaging.org/archives/2016/11/the-gender-longevity-gap-is-consistent-over-populations-and-time/

There are many possible answers to the question of why women have a longer life expectancy than men, but no real consensus on which of the candidate mechanisms are the important ones. It is interesting to note that, in an age in which rejuvenation therapies are starting to arrive, the research community has a better idea of how to bring aging under medical control, and thus make natural variations in longevity irrelevant, than of how to definitively determine the mechanisms causing those natural variations between groups of humans. Fully understanding our biochemistry is a massive undertaking, far greater in scope than merely wrestling degenerative aging into submission by addressing its root causes. Biology is enormously complex, and working with statistical demographic data or evolutionary theory doesn't tend to produce firm answers, only helping to narrow down the directions for further inquiry.

People worldwide are living longer, healthier lives. A new study of mortality patterns in humans, monkeys and apes suggests that the last few generations of humans have enjoyed the biggest life expectancy boost in primate history. The gains are partly due to advances in medicine and public health that have increased the odds of survival for human infants and reduced the death toll from childhood illness. Yet males still lag behind females - not just in humans but across the primate family tree, the researchers find. "The male disadvantage has deep evolutionary roots."

An international team compiled records of births and deaths for more than a million people worldwide, from the 18th century to the present. The data included people in post-industrial societies such as Sweden and Japan, people born in pre-industrial times, and modern hunter-gatherers, who provide a baseline for how long people might have lived before supermarkets and modern medicine. The researchers combined these measurements with similar data for six species of wild primates that have been studied continuously for three to five decades, including sifaka lemurs, muriqui monkeys, capuchins, baboons, chimpanzees and gorillas. The data confirm a growing body of research suggesting that humans are making more rapid and dramatic gains than ever before seen in the primate family tree. For example, in the last 200 years life expectancy in Sweden has jumped from the mid-30s to over 80, meaning that a baby born today can hope to live more than twice as long as one born in the early 19th century. The data show that today's longest-lived human populations have a similar 40- to 50-year advantage over people who live traditional lifestyles, such as the Hadza hunter-gatherers of Tanzania and the Aché people of Paraguay.

In contrast, these modern hunter-gatherers - the best lens we have into the lives of early humans - live on average just 10 to 20 years longer than wild primates such as muriquis or chimpanzees, from which human ancestors diverged millions of years ago. "We've made a bigger journey in lengthening our lifespan over the last few hundred years than we did over millions of years of evolutionary history." One indicator of healthcare improvement is infant mortality, which strikes fewer than 3 in 1000 babies born in Sweden or Japan today. But it was more than 40 times higher for those born two centuries ago, and is still high among hunter-gatherers and wild primates.

The researchers also studied lifespan equality, a measure similar to income equality that indicates whether longevity is distributed evenly across society, or only enjoyed by a few. They found that, for both humans and wild primates, every gain in average lifespan is accompanied by a gain in lifespan equality. That is, for a population to be very long-lived, everyone must benefit more or less equally, with fewer individuals left behind. The researchers were surprised to find that the longevity of human males has yet to catch up with females, and the improvements in males aren't spread as evenly. A girl born in Sweden in the early 1800s could expect to outlive her male counterparts by an average of three to four years. Two hundred years later, despite Swedes adding 45 years to their average lifespan, the gulf that separates the sexes has barely budged. The life expectancy gender gap isn't just true for humans. Females outlived males in almost every wild primate population they looked at.

An Illustration of the Complexity of Genetic Contributions to Longevity
https://www.fightaging.org/archives/2016/11/an-illustration-of-the-complexity-of-genetic-contributions-to-longevity/

Very few genetic variants robustly correlate with longevity across different study populations, and those that do, such as variants of APOE and FOXO3A, have small effects, only visible in the mortality statistics of large numbers of people. This indicates that the genetics of longevity, the way in which variations in metabolism and the response to high levels of age-related cell and tissue damage in later life can produce modestly different mortality rates, is a matter of many thousands of tiny, interacting contributions, very sensitive to environmental factors. It appears ever less likely that there will be any easy, small number of genetic changes that can be made to humans in order to produce significant lengthening of life. Thus the study of genetics and longevity isn't the place to be looking for cost-effective ways to produce radical life extension of decades and more. This paper is one of many recent illustrations of this point; none of the described problems would be anywhere near as much of a challenge if there was a large genetic effect on aging and longevity with simple, narrow origins there to be found. That would stand out from the data much more readily.

The results of many genome-wide association studies (GWAS) of complex traits suffer from a lack of replication. Differences in population genetic structures among study populations are considered to be possible contributors to this problem. One aspect of population structure - the differences in genetic frequencies among subgroups of individuals comprising the population - was traditionally linked with the effects of population stratification. Another one - the presence of linkage disequilibrium (LD) in many parts of the human genome including those that contain causal single-nucleotide polymorphisms (SNPs) - was actively exploited in GWAS of complex traits. Methods of fine mapping following the "discovery" phase are used for evaluating causal SNPs. One could expect that the non-replication problem due to differences in LD patterns among study populations in GWAS would disappear if the detected marker SNP is a causal one, i.e., if it contributes to the variability of a trait. It turns out that the differences in LD levels around a functional SNP may still contribute to the non-replication problem.

The estimated associations in this case depend on whether the detected functional SNP is in LD with another functional SNP, the effects of these SNPs on the trait in the absence of LD (pure effects), and on the level of LD between corresponding SNP loci. This property has important consequences for interpretation of the results of genetic analyses of complex traits. In the presence of LD the estimated effects of a causal SNP may be spurious and may incorrectly characterize the biological relationships between the SNP and the trait. In contrast the pure effect of a given causal SNP estimated in the absence of LD with other such SNPs may correctly characterize the biological connections between the SNP and the trait. Therefore, for example, performing genetic analyses of African populations (that have lower levels of LD patterns for many SNP pairs than populations of European origin) has the potential to reduce bias in the estimated effects of functional SNPs on a trait caused by the presence of LD between functional loci. This condition is, however, not sufficient because of the possible presence of hidden gene/gene interaction effects, gene/environment correlations, and gene/environment interaction effects.

Human lifespan and many other aging, health and longevity related traits are multifactorial phenotypes, that is, they are affected by many genetic and non-genetic factors. The relationships between genes and these phenotypes have special features that distinguish them from other complex traits, influence methods of their genetic analyses, and affect the interpretation of the research results. The genetic variants that influence aging, health, and longevity related traits generate age dependent changes in the population genetic structure, i.e., changes in the frequencies of genetic variants and in the levels of linkage disequilibrium (LD) among them. This feature has important implications for studies focused on the replication of GWAS research findings: independent populations involved in such studies often have different genetic structures, due in part to the differences in the population age distribution at the time of biospecimen collection. As a result, the frequencies of the genetic variants associated with these traits and their LD patterns may differ even if the genetic structures in the corresponding population cohorts were the same at birth.

Detecting statistically significant associations of genetic variants with complex traits is not the end of the genetic analyses. One reason is that the relationship between a detected marker SNP and the complex trait of interest is not, necessarily, a causal one. More often these relationships serve as proxies for the real effect of some unobserved causal SNPs (due to linkage disequilibrium (LD) between the marker and causal SNPs), and, hence, do not have a direct biological effect on the phenotype. To generate insights about the biological mechanisms responsible for the trait's variability one has to identify the causal SNPs responsible for the association signal. To identify such SNPs a number of efficient fine-mapping procedures have been recommended. The main limitation of existing methods is that they seek to identify a single causal variant which is independent of (not in LD with) other causal variants. Since this is not sufficiently realistic, a new approach that allows for efficient detection of multiple causal variants has been proposed. The case where two or more causal SNPs are in LD creates additional problems for interpretation of the results of genetic association studies.

In this paper we show that the estimates of the effects of a causal SNP on lifespan depend on the genetic structure of the population under study (e.g., the level of LD of the SNP with other causal SNPs). Genetic association studies of this trait using data from populations with different LD levels are likely to produce different results. We show that differences in population genetic structures can explain why genetic variants favorable for longevity in one population appear as harmful risk factors in another population. Population structure may also be responsible for the age-specific effects of genetic variants on mortality risk. Differences in genetic structures in distinct populations may be responsible for the low level of replicability of GWAS of human aging, health, and longevity related traits.

Mapping RNA in Search of the Mechanisms of Bat Longevity
https://www.fightaging.org/archives/2016/11/mapping-rna-in-search-of-the-mechanisms-of-bat-longevity/

Both birds and bats have great longevity for their size in comparison to mammalian species that do not fly, which has led researchers to theorize that the metabolic demands of flight lead to the evolution of cell structures that are more resistant to the damage of aging. Energy metabolism revolves around the mitochondria, the power plants of the cells, and so this in turn points to an important role for mitochondrial function and damage to mitochondria in determining aging and longevity, both across species and in individuals. There are good correlations between mitochondrial composition, the degree to which mitochondrial structures can resist oxidative damage, and mammalian life span, for example. Researchers here take a more reductionist approach to the question of why bats are exceptionally long-lived, and begin by mapping the RNA of a bat species:

Of all mammals, bats possess some of the most unique and peculiar adaptations that render them as excellent models to investigate the mechanisms of extended longevity and potentially halted senescence. They are considered the 'Methusalehs' among mammals due to their exceptional and surprising longevity given their body size and metabolic rate. Typically mammals that are small have a high metabolic rate (e.g. shrews) and do not live for a long time. However, despite their small size and high metabolic rate bats can live for an exceptionally long time, with the oldest recorded Brandt's bat (wild caught as an adult) ever recaptured being more than 41 years old with a body weight of 7 grams. Indeed, to get a positive correlation between longevity and body size in mammals, bats must be removed from the analyses. By comparing the ratio of expected longevity to that predicted from the 'non-bat placental mammal' regression line (longevity quotient - LQ) only 19 species of mammals are longer lived than man, one of these species being the naked mole rat and the other 18 are bats. This suggests that bats have some underlying mechanisms that may explain their exceptional longevity.

MicroRNA (miRNA) are a subset of short endogenous non-coding RNA that play a significant role in post-transcriptional regulation, via repression of translation. Since the first miRNA was discovered in 1993, a multitude of miRNA have subsequently been identified, and implicated in the regulation of the vast majority of biological pathways including cell cycle regulation, metabolism, tumorigenesis, as well as immune response. However, the role of miRNA regulation in mammalian ageing and the onset of age-related diseases has only recently been established. In mammals, various miRNA have been shown to be differentially expressed during ageing, most of which appear to be generally tissue-specific. In addition to tissue-specific ageing, it is increasingly evident that many miRNA regulate gene expressions in well-known ageing pathways, most notably in the p53 tumor suppressor pathway and insulin-like growth factor signaling pathway.

Despite being the second largest order of mammals (~1200 species), there is a scarcity of genomic and transcriptomic bat resources. To date, only five well-annotated bat genomes are publically available. Phylogenomic studies of bat genomes and other mammalian species reveal that a number of genes are under positive selection in bats. These genic adaptations have been correlated with traits such as echolocation, powered flight, hibernation, immunity and longevity. For example, specific non-synonymous mutations in GHR and IGF1R, key ageing-related genes, were detected in several long-lived vespertilionid bats (M. brandtii, M. lucifugus and Eptesicus fuscus), while a large proportion of genes involved in DNA repair (RAD50, KU80, MDM2, etc.) and the NF-кB pathway (c-REL and ATM2, etc.) were reported to be under positive or divergent selection in M. davidii and P. alecto. These results suggest bats may better detect and repair DNA damage. Intriguingly, positive selection was also detected in mitochondrial-encoded and nuclear-encoded oxidative phosphorylation genes in bats, which may explain their efficient energy metabolism necessary for flight. Apart from comparative genome analysis, only a small number of transcriptomic studies on bats using have been carried out, focused primarily on the characteristics of hibernation, immunity, echolocation and phylogeny. However, the molecular mechanisms of adaptations affecting longevity are still far from understood, especially with respect to gene regulation.

In the present study, we sequenced six small RNA libraries from whole blood sampled from wild-caught greater mouse-eared bats (Myotis myotis) and for the first time made genome-wide comparisons of both miRNomes and mRNA transcriptomes between bat and non-bat mammalian species (human, pig and cow). The profiling of the M. myotis blood miRNome showed a large number of bat-specific miRNA involved in regulating important pathways related to immunity, tumorigenesis and ageing. Comparative analyses of both miRNomes and transcriptomes also revealed distinctive longevity mechanisms in bats. Several up-regulated miRNA possibly act as tumor suppressors. Gene Ontology (GO) enrichment analysis of differentially expressed protein-coding genes showed that up-regulated genes in bats compared to other mammals were mainly involved in mitotic cell cycle and DNA damage repair pathways while a high number of down-regulated genes were enriched in mitochondrial metabolism. The results and data presented here show unique regulatory mechanisms for protection against tumorigenesis, reduced oxidative stress, and robust DNA repair systems, likely contribute to the extraordinary longevity of bats.

Comments

Post a comment; thoughtful, considered opinions are valued. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.