One of the reasons why the idea of rejuvenating people isn't all that easy to sell is that it challenges the status quo. For good or bad, we're used to the fact that our health goes south on us as time goes by, ultimately killing us if nothing else does. That's not a nice certainty to have, but our species is one of planners; we tend to prefer bad certainties to uncertainty. For example, some people want to be certain that, at some point, they won't be fit for work anymore and will need to retire; they prefer this over the uncertainty of not knowing how they'd make a living at age 150.

That's not the only reason. Radical change requires radical rethinking of anything affected by the change itself; as rejuvenation would affect our social contracts, the job market, future planning, our idea of life milestones, of family, what it means to be old, and many other things, it would take a lot of rethinking - which is something humanity generally does only grudgingly and on its own sweet time.

Think about it: "Granny" is more likely to make you think of a sweet, gray-haired lady with large glasses on her nose baking a cake than of an attractive girl out one late night with friends. Yet, in a world in which comprehensive rejuvenation is common, the granny and grandpa that inhabit our collective imagination would simply not exist; rather, you'd find that grannies and grandpas in their late 80s can't be told apart from people in their 20s; elderly would look just as young as "truly young" people, would be just as healthy, and would be engaged in the activities they prefer rather than having their activities limited by their declining health.

This is only one example out of many more new situations that we, having grown up in a world plagued by aging, would have to get used to; newer generations born in a post-aging world would hardly have any problem with it and would probably end up wondering how anyone could possibly have opposed it in the past. Examples like this are different from concerns such as overpopulation in that they don't represent a potential but tangible issue that might arise as a consequence of rejuvenation; people may have problems with biologically young elderly people simply because they're new and unfamiliar ideas, not because they pose any actual problem.

The Methuselah Foundation, promoting the extension of the healthy human lifespan for 17 years, announces the successful closing of fundraising for its boutique venture fund, Methuselah Funds LLC (M Fund). The M Fund is mission-oriented and focused on seed-stage companies that have technology to increase the healthy human lifespan in multiple ways. The investment thesis of the M Fund is based around six pathfinding strategies that provide a structure to how the Fund believes healthy longevity can be achieved. These strategies have been purposefully named in a non-academic way in order to explain the thought process via analogies and recognizable ideas. These strategies and the details are:

1) New Parts for People - As we age, the wear and tear we put on our bodies begins to take a toll. As one body component begins to weaken, this leads to an exponential strain on the body that stresses remaining parts, leading to failure and eventual death. This strategy focuses on technologies that create replacement parts of our bodies, such as organs, cartilage, bones, and vasculature.

2) Get the Crud Out - Cellular processes of life result in by-products that are harmful if not cleared by the cell. As we age, there is an increasing amount of DNA damage and accumulation of wastes, which negatively affect cellular and organ function. This strategy focuses on technologies that clear harmful substances from the body at both the microscopic (cellular), and macroscopic (organ) level.

3) Restore the Rivers - As an individual ages, the vascular system becomes less effective due to vessel stiffening, less effective pumping, insufficient waste clearance, poor oxygen exchange, and inadequate angiogenesis. This affects every process of the body, down to the sub-cellular level. This strategy addresses the need to restore the circulatory system to youthful competence.

4) Debug the Code - The code includes DNA, and also the "action code", RNA, and proteins that actually do the work of the cells, which become damaged and altered with age. This strategy deals with the informational life of the cell and its expression.

5) Restock the Shelves - As we age, stem cells become fewer and less effective, senescent cells become more prolific, and the immune system becomes weakened. This strategy addresses the need to provide the aged body with the tools required to rebuild and protect itself.

6) Lust for Life - Among the aged, depression, loss of purpose, loss of senses, loss of independence, and social isolation are serious problems. This strategy addresses the need to help elderly patients want to increase their longevity, and to empower them to make the most of longer life.

The M Fund was conceived after successful angel mission-focused investments by the Methuselah Foundation. These include being the lead investor in the seed-stage round of Organovo Holdings, Inc, a medical laboratory and research company which designs and develops functional, three-dimensional human tissue for medical research and therapeutic applications. Investment in the longevity field is heating up significantly and the M Fund anticipates that investments will begin pouring into the area over the next 18 months. The M Fund's current portfolio companies include:

OncoSenX - A pre-clinical cancer company that targets solid tumors based on transcriptional activity using a unique lipid nanoparticle and plasmid DNA. OncoSenX is working on the next generation in cancer therapy that will be more targeted and with fewer side effects. Their treatment delivers a simple program that induces apoptosis in cancerous cells.

Leucadia - Has a unique and compelling approach on how to potentially predict, halt, and cure early stage Alzheimer's disease. 25 years of research have focused on plaques and tangles as the cause of AD. At Leucadia, it is known that those are previously undiscovered pathological effects of a more serious underlying condition. Leucadia's technology may allow for the creation of a simple, yet sophisticated surgical procedure bypassing the unsuccessful small-molecule approach.

Oisin - Their research and platform technology demonstrate that one of the solutions to mitigating the effects of age-related diseases is to address the damage resulting from the aging process itself. Oisín is developing a highly precise, DNA-targeting platform to clear senescent cells. Oisín's platform has shown as much as an 80% reduction in senescent cells in cell culture and significant reductions of senescent cell burden in naturally aged mice.

Revercell - Is developing global and transformational epigenetic solutions, moving past the single gene/pathway manipulations of traditional approaches, to address the multifaceted manifestation of cellular age, with tissue and organ level benefit. The company is developing the technology to effectively turn mature differentiated cells to a dramatically younger state, without first turning them into totipotent or pluripotent cells.

Aging is one of the most powerful independent risk factors for the development of atherosclerosis. Among many other explanations, this could be driven by age-related changes in the immune system. Systemic inflammation contributes to atherogenesis and an increased low-level inflammation during the aging process ("inflammaging") has been proposed as a culprit for many age-related diseases. Monocyte-derived macrophages are the most abundant immune cells in atherosclerotic plaques, and are key to the formation, growth, and rupture of these lesions. Monocyte production capacity for several pro-atherogenic inflammatory cytokines was higher with increasing age.

In the past few years, three novel mechanisms have been proposed to contribute to this age-related activation of the innate immune system. First, cellular senescence, a permanent arrest of cell growth, is associated with an enhanced secretion of pro-inflammatory mediators, e.g. cytokines. Secondly, due to an accumulation of acquired mutations in hematopoietic stem cells that confer a competitive advantage, more than 10% of subjects aged over 70 years have significant amounts of mutant clones in peripheral leukocytes, which is called clonal hematopoiesis of indeterminate potential (CHIP). CHIP is associated with an increased risk for cardiovascular disease because these clonal leukocytes have an increased NLRP3 inflammasome-mediated interleukin-1β secretion. Thirdly, we and others have described that innate immune cells can effectively build a non-specific immunological memory that results in an increased proinflammatory phenotype, a process which is termed trained immunity.

Recent studies have shown that circulating monocytes and myeloid progenitor cells in the bone marrow have the intriguing capacity to reprogram towards a long-term non-specific pro-inflammatory phenotype following initial exposure to microorganisms or microbial products. Although beneficial in the context of resistance against reinfections, this mechanism might be detrimental in non-infectious chronic inflammatory conditions in which myeloid cells contribute to disease progression, such as atherosclerosis. We have recently proposed this mechanism to contribute to the well-known association between acute and chronic infections and atherosclerosis. Interestingly, trained immunity is not only induced by microbial products, but also by endogenous sterile atherogenic stimuli such as oxidized low-density lipoprotein (oxLDL) or lipoprotein(a).

Olshansky discusses how human longevity has reached into its upper limits and has little room for further gains. He notes that at the turn of the 20th century, life expectancy at birth in most developed nations ranged from 45 to 50 years. With the emergence of major public health initiatives by the end of the 19th century - including sanitation and the public provision of clean water - mortality rates dropped, and life expectancy increased rapidly. The rise in longevity has slowed considerably in recent decades, and maximum lifespan has never changed much throughout human history.

"There's been a lot of focus in the news lately about what is the maximum human lifespan, with some researchers claiming that it has the potential to be infinite, but there is a biologically based limit imposed largely by the way in which our bodies are designed, and it can be expressed mathematically." Based on the science and medicine available today, he contends that the probability of any significant increase in maximum lifespan in this century is remote.

"There is reason to be optimistic that future breakthroughs in aging biology, if pursued, could allow humanity to live healthier longer. You don't want to live to be over 100 years old if the last 20 years of your life are spent in pain and sickness. Ideally, you want to compress the years of decay and disease - what I call the 'red zone' - into as few as possible at the very end of life. We should not continue to pursue life extension without considering the health consequences of living longer lives. This will be the only way science can push through the biological barriers to life extension that exist today. Life extension should no longer be the primary goal of medicine when applied to people over age 65 - the principal outcome and most important metric of success should be extension of the healthspan."

Over the past century, the relatively easy gains in life expectancy have been achieved by reducing mortality of younger people; more recently, scientists have focused on how much higher life expectancy can increase and what the maximum lifespan is for humans. The former is a population-based metric that involves national vital statistics for groups of people; the latter is the world record for longevity held by 1 person. Regarding maximum lifespan, only a small proportion of all humans are capable of living to 115 years of age. As such, the probability of any substantial increase in maximum lifespan in this century is remote.

Regarding life expectancy, one view developed in 1990 suggested that the increase in life expectancy would soon decelerate because the easy gains had already been achieved. Any substantive future increases require improvements in mortality at older ages, although components of the human body (e.g., brain, heart, knees) are not designed for long-term use. Others suggested that historical trends in the increase in life expectancy will continue indefinitely into the future due to yet-to-be-developed medical advances and improved lifestyles. Not one of the anticipated high-life-expectancy scenarios is remotely plausible today. In fact, a new trend in the opposite direction has emerged in much of the developed world, indicating that death rates for many major causes of death have either leveled off, experienced declining improvement, or increased since 2008.

Reductions in childhood diseases can occur only once for a population; once such gains are achieved, the only outlets for further gains in life expectancy must come from extending the lives of older people. Given that multiple fatal conditions accrue in older people because of biological aging. Once survival past age 65 years becomes common in a country, life expectancy gains will decelerate, even with medical advances and improved lifestyles. Because the point of diminishing returns on life expectancy and the longevity limit for the species has been approached in many parts of the world, there is good reason to conclude that the goal of life extension has largely been achieved.

The conventional approaches used to counteract the diseases of older age have been to improve behavioral risk factors, find ways to detect them earlier, and use medical technology to extend survival for those who already have diseases. The more important goal of public health, medicine, biotechnology, and the health sciences should now shift toward delaying and compressing the period of the lifespan when frailty and disability increase substantially. Referred to as the first health revolution, this new approach for public health (which is to target aging) is seen as a highly effective method of primary prevention.

A consortium of scientists as well as public health experts and organizations has formed with the purpose of developing this new approach to extend healthspan, address the diseases of aging, and help to ameliorate the economic challenges of an anticipated rising prevalence of late-onset diseases. This effort is called the Longevity Dividend Initiative or geroscience. Clinical trials designed to target aging have been approved by the US Food and Drug Administration, with the first trial set to begin in 2019. Large investments in aging biology have already begun through Google's Calico and Human Longevity Inc. The National Institute on Aging has established the Interventions Testing Program to rigorously and quickly test prospective aging interventions for free. The National Institutes of Health has reduced the barriers between its disease-oriented research silos, and the American Federation for Aging Research is spearheading a global effort to secure funds to launch the Longevity Dividend Initiative in 2019. The time has come to recognize the achievement of life extension. Efforts should be focused on achieving the goals of extending and improving the healthspan.

Hi, everyone! Time for another exciting mitochondrial update. This time, we've got 2 teasers for you. The first is that we're preparing a story about a new trick that we've discovered to improve the allotopic expression of mitochondrial genes. We're still confirming that we're 100% sure that we're right before writing up the manuscript and making an announcement, but we're very close. Yes, that means we're getting it to work on more genes. Stay tuned!

The second is that we're in the final stages of planning our first mitochondrial mouse, and we're going to ask for your help in getting it started! This will involve combining two technologies that SENS Research Foundation helped invent: an advanced transgenic mouse technology and applying what we learned from the 2016 paper to a mouse model that we think will prove to the world that mitochondrial gene therapy is the future. You should see an announcement about the new mouse project soon.

This week we are once again profiling the work at one of Longecity's affiliate labs, the SENS Research Center is leading the charge in the damage theory of aging. One part of the human system that is damaged and declines in function as we age is the cellular mitochondria. The SENS idea to fix this problem, termed MitoSENS, is one of the more ambitious and technically difficult fixes for damaged mitochondria. There have been some significant developments lately and you'll hear about them in this interview with the leader of MitoSENS, Dr. Matthew O'Connor.

I: Welcome to the program!

M: Hi, it is a pleasure to be with you. Thank you.

I: For any first time listeners, could you provide the digest version of MitoSENS?

M: Sure. We have been working on technologies to try to develop a gene therapy for mitochondrial mutations, the idea being that the mitochondria has its own DNA, its own genes, very few of them, only 13 protein coding genes, but they are all important, essential genes. They are a problem when they get mutated, either through an inherited mutation from your mother, or if you develop a mutation with age.

I: And those mutations that develop with age affect pretty much everyone, correct?

M: Exactly. We don't understand it perfectly yet, but all indications are that mitochondrial function decreases with age, and that this is an important aspect of aging that everyone feels and experiences, for example in their muscles, as they get weaker with age.

I: When we last spoke, you were just in a proof of concept stage, trying to move mitochondrial genes in to the nucleus. That's what we're talking about here, the first concept of MitoSENS was to move some of those protein coding genes into the cell nucleus, where they could be protected, and continue to do good work instead of bad work. What is the latest? Have you moved on from the original two genes you were targeting?

M: Yes, so as you point out the mitochondrial DNA is more susceptible to damage because the mitochondria is specialized into making energy, not for protecting and housing DNA. That is the job of the nucleus, which is where all of our chromosomes live. The mitochondria produce energy and the byproduct of energy production is free radicals, which DNA is pretty sensitive to. So we've been working on trying to create a backup copy for any of these thirteen protein coding genes in the nucleus. You raised the two that we had been working on and talking about for a while. We published something on those two at the end of 2016, and so that went very well, we were able to show clearly that we could take the cell that was taken from a patient who had a mutation in two of the thirteen genes, and rescue that mutation by performing our gene therapy in a petri dish of these cells. We could make them behave and survive more like normal cells.

I: So you were able to fix some mitochondrial mutation, rescue some mitochondrial function in those cells. That sounds pretty big.

M: Yes, so it was very clear that by a number of measures. We could show the mitochondrial energy production, we could show the mitochondrial oxygen consumption - the reason that we breathe, that we consume oxygen, is that our mitochondria need it for energy production. We could show that their survival improved. We could grow the cells under two different conditions: the conditions in which the cells could survive without oxygen, growing anaerobically, the way cancer cells usually do, or the way bacteria grow, or we grew them under conditions where they could only survive aerobically, if they could consume oxygen using the mitochondria. Under those conditions only the rescued cells survived, and the mutant cells all died.

I: So you had some success with those first two genes that you were focusing on. What about the other 11 genes? Any plans to work on any of those any time soon?

M: Yes, in fact we are already working on all of them to various extents, and I can tell you a little bit about that. We've made constructs for all of the, meaning we've designed DNA targeting vectors for all 13 of the protein coding genes, and we've tested them to various extents for their ability to produce the gene products to send them to the mitochondria. We've had varying levels of success, so they are not all working sufficiently well yet that we can declare victory and go home. But we will have some new progress to report soon on all of them, I think. We'll show which ones are working best and which ones are working less well. We'll be able to talk about strategies that we are working on to improve the continuous process of engineering these genes for targeting to the mitochondria.

I: Now I'm not a bioengineer, so could you explain the mechanism by which genes that might be sent to the nucleus and encode mitochondrial proteins, how do those proteins end up back at the mitochondria? How does that happen?

M: So the mitochondria only codes 13 proteins, the nucleus codes over a thousand proteins that go to the mitochondria. That is more the normal course of events, whereas the weird part is making proteins in the mitochondria. What we've done is we've studied the way that the nucleus does the job normally, and are trying to adapt the mitochondrial proteins to act more like the nuclear ones. The two simplest components of that are that, for one, the mitochondrial DNA is written in a slightly different language than the nuclear DNA. They still use the same four bases, A, T, C, and G, but the way you read that string of letters is slightly different. The first thing we need to do is to translate that into a language that the nucleus understands. The second thing that we have to do is put a targeting sequence on the front of the gene, and this is called a mitochondrial targeting sequence. We pick one or more to test, and we've tested many in our lab, of these sequences, and move them from a different gene to be in front of any of these 13 mitochondrial genes, and use that to target the product to the mitochondria.

I: That sounds pretty difficult, technically speaking. You've been working on it for a few years now, what is the biggest challenge in terms of speeding along this potential therapy to rejuvenate the human body?

M: Actually, the two things I just laid out are relative the easy part, and the hard part is optimizing the way the code works with the targeting sequence, and then other kinds of regulatory sequences that surround the gene, upstream and downstream of the gene, where the gene goes into the genome, how many times it is inserted. There are a lot of different aspects to this that we are playing with that end up being the difficult part, and understanding how evolution has created this system, and figuring out how we can adapt it to the mitochondrial genes. We are constantly engineering and reengineering, trying different little tweaks to the sequence of these genes, in order to to try to figure out how to improve the production of the gene product, the targeting to the mitochondria, and then the import into the mitochondria, and then measuring whether or not it is behaving functionally.

I: People who follow rejuvenation research, such as the stuff that you are doing, know that it is slow, it is tedious, and this kind of work is very complicated. Are there any new tools that you see arriving on the scene that might help produce results more efficiently?

M: There are two tools that are helping us right now. One is that in the current era of synthetic biology, when we have more and more tools to create new DNA sequences, such that today, it is relatively affordable, a cost in the hundreds to low thousands, to have a company synthesize any DNA sequence that we want to test just from scratch. So these days, as opposed to when I was in graduate school, we can just type on a computer the code that we want to create, and have it synthesized. In the old days, we had to use a lot of fancy tricks that would take up weeks and months of a scientist's time, to create a new version, but these days it is becoming more and more affordable just to type it out and send it off. That has been a huge boon to us, and our ability to test new ideas. A second one is CRISPR, and this is something new, not to molecular biology, but new to this project, that is allowing us to control where in the nuclear genome we are inserting our sequences. That takes out a variability that traditionally scientists have had to content with, where when you are trying to insert your gene of interest into the genome, usually it goes in randomly, anywhere, and that is an aspect that can complicate things. We are now starting to control this by inserting genes more specifically using CRISPR.

I: Anyone who begins any kind of research project into rejuvenation, there are a lot of companies out there nowadays, they look at one aspect of aging, and it seems all of a sudden there crop up a few roadblocks or unexpected things along the way. I know you've been very careful in planning out how MitoSENS is going to progress. Over the past few years, what has been the most surprising thing, or roadblock that you didn't anticipate?

M: One problem that we have is that the models that are available to study mitochondrial mutations and mitochondrial disease are quite limited. For example, I was just talking about using CRISPR to target nuclear DNA specifically. Now for inserting our sequences, that's great, but if you wanted to target something into the mitochondria, you can't use CRISPR, it doesn't work there, or at least no-one has figured out how to make it work there. So there's no way to manipulate the mitochondrial genome, and that means that no-one can create custom mutations in mitochondrial DNA. We are left with random mutations that occur naturally. Furthermore, there aren't very many models of these mutations in model systems that are usually studied in the labs, like mice. There are very few mouse models of mitochondrial disease available, and so most of us actually use humans. That doesn't mean that we're experimenting on people, but we do use human cells. We are restricted to cells that are collected from patients who have these very rare mitochondrial mutations, and to make that even a little bit more rare, our group is picky about the kind of mutations that we want to study, because we want constrained mutations that only affect one, maybe two genes at a time, so that we can ask and answer simple questions. Trying to do everything all at once turns out to be a messy and careless way of doing things, and doesn't produce results very quickly. I'd say that has been one of the biggest roadblocks slowing us down, a lack of good cell lines to work with. We're always on the lookout in the literature and at conferences for the right kind of cells to work on.

I: That does give me a followup question: when do you anticipate that you will be working with whole organisms rather than just with cells in a petri dish?

M: Great question, and I have an encouraging answer for you. We are planning on launching some fundraising for a mouse project in the coming months. We are writing up funding proposals for this as we speak. We have quotes from a transgenic mouse facility that could produce the mice for us. We have fully designed the mice we want to make. What I said before, that it is rare to find mice that have these mutations, we have found one. It is not as dramatic of a mutation as the ones that we usually work on in the cell lines, but if it was then the mouse probably wouldn't be around to be talking about it, because mitochondrial mutations are so damaging to health. But we have one that does have a mild mutation, and we've already done the experiments on the cells from this mouse, and they are deemed to be working. So I think we're going to have mice fairly soon, but it will be a couple of years before we have progress to report in terms of figuring out whether we've actually rescued the mutation. Nonetheless, we should have mice with our gene in maybe less than a year.

I: That sounds great. A final question here: you work with damaged mitochondria and the SENS theory of aging says, hey, let's just fix the damage and things are going to get a lot better. Do you have any thoughts on a lot of the current products that are out there that people take, supplements that supposedly target mitochondrial function? Antioxidants like MitoQ, or NAD precursors - what do you think about them? Do you think there is much efficacy with some of these supplements?

M: It is a difficult question for me, as it is not my main area of expertise, but I can opine on it a bit. I would say that there is some tentative, encouraging research suggesting that boosting your NAD levels through one or more of these supplements that are available might actually be having some beneficial effects on your mitochondrial function. Whether or not that is going to help you to stay healthy longer or live longer, I think is far from a settled question yet. But they might be modestly boosting mitochondrial energy production. Then the mitochondrially targeted antioxidants I would also say are tentatively encouraging, but I don't want to recommend that people run out and start dosing themselves with it, but I do think it is an area of research worth keeping your eyes on. A generation past, an era in which everyone was talking about taking megadoses of vitamin C and vitamin E to try to soak up all the free radicals being produced by mitochondria, it turns out that those don't get into your mitochondria efficiently, but some of these targeted ones do seem to get into your mitochondria. The hesitation is that this is a sensitive system, that you don't want to mess around with too much. There have been experiments that have shown that some of these targeted antioxidants can do too good of a job and actually end up damaging the function of mitochondria in some of these cases. So I'm going to sit tight before I start taking a lot of these supplements, but I am keeping my eye on the research.

A study has found that certain genes and pathways that regulate splicing factors - a group of proteins in our body that tell our genes how to behave - play a key role in the ageing process. Significantly, the team found that disrupting these genetic processes could reverse signs of ageing in cells. Aged, or senescent, cells are thought to represent a driver of the ageing process and other groups have shown that if such cells are removed in animal models, many features of ageing can be corrected. This new work found that stopping the activity of the pathways ERK and AKT, which communicate signals from outside the cell to the genes, reduced the number of senescent cells in in cultures grown in the laboratory. Furthermore, they found the same effects from knocking out the activity of just two genes controlled by these pathways - FOXO1 and ETV6.

The ERK and AKT pathways are repeatedly activated throughout life, through aspects of ageing including DNA damage and the chronic inflammation of ageing. The research suggests that this activation may hinder the activity of splicing factors that tell genes how to behave. This, in turn, could lead to a build-up of senescent cells - those which have deteriorated or stopped dividing as they age. To stop the activity of the ERK and AKT pathways, the study used inhibitors which are already used as cancer drugs in clinics. When the pathways were disrupted, the team observed an increase in splicing factors, meaning better communication between protein and genes. They also noted a reduction in the number of senescent cells. Researchers saw a reversal of many of the features of senescent cells that have been linked to the ageing process.

The regenerative capacity of peripheral nerves declines during aging, contributing to the development of neuropathies, limiting organism function. Changes in Schwann cells prompt failures in instructing maintenance and regeneration of aging nerves; molecular mechanisms of which have yet to be delineated. Here, we identified an altered inflammatory environment leading to a defective Schwann cell response, as an underlying mechanism of impaired nerve regeneration during aging.

Chronic inflammation was detected in intact uninjured old nerves, characterized by increased macrophage infiltration and raised levels of monocyte chemoattractant protein 1 (MCP1) and CC chemokine ligand 11 (CCL11). Schwann cells in the old nerves appeared partially dedifferentiated, accompanied by an activated repair program independent of injury. Upon sciatic nerve injury, an initial delayed immune response was followed by a persistent hyperinflammatory state accompanied by a diminished repair process. As a contributing factor to nerve aging, we showed that CCL11 interfered with Schwann cell differentiation in vitro and in vivo.

Our results indicate that increased infiltration of macrophages and inflammatory signals diminish regenerative capacity of aging nerves by altering Schwann cell behavior. The study identifies CCL11 as a promising target for anti-inflammatory therapies aiming to improve nerve regeneration in old age.

The large ASPirin in Reducing Events in the Elderly (ASPREE) trial is intended to determine the risks and benefits of daily low-dose aspirin in healthy older adults without previous cardiovascular events. Initial results show that aspirin did not prolong healthy, independent living (life free of dementia or persistent physical disability). Risk of dying from a range of causes, including cancer and heart disease, varied and will require further analysis and additional follow-up of study participants.

ASPREE is an international, randomized, double-blind, placebo-controlled trial that enrolled 19,114 older people (16,703 in Australia and 2,411 in the United States). The study began in 2010 and enrolled participants aged 70 and older; 65 was the minimum age of entry for African-American and Hispanic individuals in the United States because of their higher risk for dementia and cardiovascular disease. At study enrollment, ASPREE participants could not have dementia or a physical disability and had to be free of medical conditions requiring aspirin use. They were followed for an average of 4.7 years to determine outcomes.

In the total study population, treatment with 100 mg of low-dose aspirin per day did not affect survival free of dementia or disability. Among the people randomly assigned to take aspirin, 90.3 percent remained alive at the end of the treatment without persistent physical disability or dementia, compared with 90.5 percent of those taking a placebo. Rates of physical disability were similar, and rates of dementia were almost identical in both groups.

The group taking aspirin had an increased risk of death compared to the placebo group: 5.9 percent of participants taking aspirin and 5.2 percent taking placebo died during the study. This effect of aspirin has not been noted in previous studies; and caution is needed in interpreting this finding. The higher death rate in the aspirin-treated group was due primarily to a higher rate of cancer deaths. A small increase in new cancer cases was reported in the group taking aspirin but the difference could have been due to chance. As would be expected in an older adult population, cancer was a common cause of death, and 50 percent of the people who died in the trial had some type of cancer.

The researchers also analyzed the ASPREE results to determine whether cardiovascular events took place. They found that the rates for major cardiovascular events - including coronary heart disease, nonfatal heart attacks, and fatal and nonfatal ischemic stroke - were similar in the aspirin and the placebo groups. In the aspirin group, 448 people experienced cardiovascular events, compared with 474 people in the placebo group.

Bone is a living tissue that is repeatedly broken down (bone resorption) and remade (bone formation) little by little every day. If this balance collapses and bone resorption exceeds bone formation, bone density decreases and can lead to osteoporosis. Sirtuins are enzymes that play important roles in controlling aging, stress responses, various areas of the metabolism, and several other body functions. In mammals, there are seven types of sirtuins, SIRT1 to SIRT7. Although SIRT7 has been reported to be involved in cancer and lipid metabolism, its role in bone tissue and bone aging was unknown.

Recent experiments showed that mice lacking the SIRT7 gene had reduced bone mass. Analysis showed that bone formation and the number of osteoblasts (bone-building cells) had been reduced. Furthermore, the researchers obtained similar results using osteoblast-specific SIRT7 deficient mice, thereby showing that osteoblast-specific SIRT7 is important for bone formation. To clarify the mechanism, the researchers compared sirtuin (SIRT1, 6, and 7) expression in the skeletal tissue of young and old mice, and found that SIRT7 decreased with age. Additionally, the expression of genes indicating osteoblast differentiation was also decreased, thereby revealing that SIRT7 controls the differentiation of osteoblasts.

Researchers found that the transcription activity of SP7 (also known as Osterix), a protein known to induce differentiation of pre-osteoblasts into mature osteoblasts and osteocytes, was markedly decreased in osteoblasts that lacked the SIRT7 gene. "In situations where SIRT7 does not work sufficiently, such as in an older individual, osteoblast formation is impaired due to low SP7/Osterix transcriptional activity. We believe that this decreased osteogenesis is associated with osteoporosis. Our results show that the regulatory pathway of SIRT7 - SP7 / Osterix is a promising target for new therapeutic agents to treat decreased osteogenesis and osteoporosis."

Intrinsic insufficiencies in cellular catabolism and transport, particularly in post-mitotic and senile cells, lead to the build up of specific compounds that exert deleterious effects on cellular function and viability. One example of accumulation of pathogenic compounds is the formation of transformed oxysterols that exhibit cytotoxicity towards mammalian cells and are shown to participate in the pathogenesis of several age-related diseases. The major intracellular cholesterol oxide, 7-ketocholesterol, has been involved in pathogenesis of age-related diseases such as atherosclerosis, Alzheimer's disease, Parkinson's disease, and cancer. This compound is a natural oxysterol produced via autooxidation of cholesterol and cholesterol-fatty acid esters and mainly found in oxidized lipoprotein deposits associated with atheromatous plaques.

Therefore, the delivery of microbial sterol-catabolizing enzymes into affected cell types may be advantageous for controlling elevated 7-ketocholesterol levels, and consequently help to reduce the severity of the diseases associated with the accumulation of this oxysterol. Several human enzymes are capable of metabolizing 7-ketocholesterol, but the main limitation is their localization in cellular compartments other than the lysosomes that makes them not very efficient at preventing lysosomal membrane permeabilization as well as resulting death-signalling cascade. The goal of this study was to isolate the microorganisms with high catabolic activity towards 7-ketocholesterol from diverse environmental samples (sea water sediment, soil, manure piles).

Four bacterial isolates, showing high catabolic activity towards 7-ketocholesterol were isolated: Alcanivorax jadensis IP4 (sea water sediment), Streptomyces auratus IP2 (soil), Serratia marcescens IP3 (soil) and Thermobifida fusca IP1 (manure piles). All the isolates were capable of utilizing 7-ketocholesterol as the sole organic substrate, resulting in its mineralisation. Overall, these results support the notion that oxysterol levels might be controlled by biodegradation processes, and further investigation of specific microbial enzymes involved in catabolism as well as the specific pathways involved in microbial 7-ketocholesterol degradation can be the next goals leading to come up with identifying enzymes capable of transforming oxysterols for potential environmental, industrial, pharmaceutical, and medical applications.

"There is big interest in the relationship between osteoporosis and dementia. This study is the first to address this question in a very large database enabling the case-control-comparison between patients with and without osteoporosis." This retrospective cohort study used data from the Disease Analyzer database (IQVIA), which compiles information on drug prescriptions, diagnoses, and demographic data obtained directly and in anonymous format from computer systems used by general practitioners and specialists. This database has already been used in several studies focusing on osteoporosis and dementia in recent years.

The study included patients diagnosed with osteoporosis between January 1993 and December 2012 (index date) and were followed for up to 20 years. After applying similar inclusion criteria, controls were matched (1:1) to osteoporosis patients using propensity scores based on age, gender, index year, several comorbidities, and co-therapies. The main outcome of the study was to determine the proportion of patients with all-cause-dementia diagnoses within 20 years of the index date.

The study included 29,983 patients with osteoporosis and 29,983 controls without osteoporosis. After 20 years of follow-up, 20.5% of women with osteoporosis and 16.4% of controls had been diagnosed with dementia. At the end of the follow-up period, dementia was found in 22.0% of men previously diagnosed with osteoporosis and 14.9% of men without this chronic condition. Osteoporosis was associated with a 1.2-fold increase in the risk of being diagnosed with dementia in women and a 1.3-fold increase in the risk of being diagnosed with dementia in men.

"The major hypothesis to explain the association between osteoporosis and dementia is that these two conditions have similar risk factors. These factors include APOE4 allele of the apolipoprotein E, a major cholesterol carrier, lower vitamin K levels, vitamin D deficiency, but also androgens and estrogens." The main limitations of the study are missing data on bone mineral density and on lifestyle-related risk factors (e.g., smoking, alcohol, and physical activity).

As mammals age, immune cells in the brain known as microglia become chronically inflamed. In this state, they produce chemicals known to impair cognitive and motor function. That's one explanation for why memory fades and other brain functions decline during old age. Dietary fiber promotes the growth of good bacteria in the gut. When these bacteria digest fiber, they produce short-chain fatty acids (SCFAs), including butyrate, as byproducts. "Butyrate is of interest because it has been shown to have anti-inflammatory properties on microglia and improve memory in mice when administered pharmacologically."

Although positive outcomes of sodium butyrate - the drug form - were seen in previous studies, the mechanism wasn't clear. A new study reveals, in old mice, that butyrate inhibits production of damaging chemicals by inflamed microglia. One of those chemicals is interleukin-1β, which has been associated with Alzheimer's disease in humans. Understanding how sodium butyrate works is a step forward, but the researchers were more interested in knowing whether the same effects could be obtained simply by feeding the mice more fiber.

The concept takes advantage of the fact that gut bacteria convert fiber into butyrate naturally. Butyrate derived from dietary fiber should have the same benefits in the brain as the drug form, but no one had tested it before. The researchers fed low- and high-fiber diets to groups of young and old mice, then measured the levels of butyrate and other SCFAs in the blood, as well as inflammatory chemicals in the intestine. "The high-fiber diet elevated butyrate and other SCFAs in the blood both for young and old mice. But only the old mice showed intestinal inflammation on the low-fiber diet. It's interesting that young adults didn't have that inflammatory response on the same diet. It clearly highlights the vulnerability of being old." On the other hand, when old mice consumed the high-fiber diet, their intestinal inflammation was reduced dramatically, showing no difference between the age groups. The researchers examined about 50 unique genes in microglia and found the high-fiber diet reduced the inflammatory profile in aged animals.

It is known that salicylates have beneficial activity on several pathways implicated in inflammation. For example, acetylsalicylic acid (ASA) is known to act as an anti-inflammatory. Interestingly, salicylates and other nonsteroidal anti-inflammatory drugs were also shown to extend lifespan of yeast and fly through inhibition of tryptophan uptake. Salicylates have also been shown to activate the adenosine monophosphate-activated protein kinase (AMPK) pathway, which has been suggested to control the aging process in general. Targeting AMPK has been discussed as a potential strategy to slow down aging in humans.

Interestingly, ASA has recently been revealed as a lifespan-extending treatment in both mice and nematodes. Salicylic acid also extends lifespan of C. elegans, albeit with a less pronounced effect than ASA. Work on the molecular mechanism in C. elegans has shown that activation of AAK-2/AMPK and DAF-16/FOXO was required for the lifespan-extending activity of ASA. These results led us to investigate in the present work another salicylic acid derivate, 5-octanoyl salicylic acid (referred to as C8-SA).

Unlike for ASA or salicylic acid, no anti-inflammatory activity has been detected for C8-SA. However, we were able to show that C8-SA displays a similar activity to ASA with regard to lifespan in the roundworm Caenorhabditis elegans. C8-SA activates AMPK and inhibits TOR both in nematodes and in primary human keratinocytes. We also show that C8-SA can induce both autophagy and the mitochondrial unfolded protein response (UPRmit) in nematodes. This induction of both processes is fully required for lifespan extension in the worm. In addition, we found that the activation of autophagy by C8-SA fails to occur in worms with compromised UPRmit, suggesting a mechanistic link between these two processes.

Mitochondria play key roles in regulating the ageing process. When their membrane potential and function declines, their production of adenosine triphosphate (ATP) reduces and they can signal cell death. This is particularly marked in the energy demanding central nervous system, where the neurons and glia, undergo some key structural and functional changes during ageing.

Recently, photobiomodulation, the application of red to infrared light on body tissues has been reported to alter the course of aged decline. These wavelengths are absorbed by cytochrome c oxidase, the rate limiting enzyme in mitochondrial respiration, increasing its activity along with mitochondrial membrane potential and ATP production. For the neurons, photobiomodulation improves function, as measured by electroretinograms, in the retina of aged mice, together with reducing cell death in a range of experimental pathologies in the brain.

The precise mechanisms used by photobiomodulation are unclear. Mitochondrial and physiological functions are improved, but increased ATP production alone is unlikely to underpin the physiological improvement, as this is relatively temporary. Hence, there are likely to be cascades of signalling between mitochondria and other structures including the nucleus and endoplasmic reticulum that have a wide ranging impact on metabolism that sustain longer term positive changes. For the neurons, several studies have reported that photobiomodulation activates various transcription factors leading to the expression of stimulatory and protective genes related to beneficial cellular features, for example neurogenesis, synaptogenesis, and an increase in neurotrophic growth factors. For the glial cells, the mechanisms are less clear.

A key issue for consideration at this point is whether the photobiomodulation-induced benefits seen in the animal models of ageing can be translated to humans. One problem would be method of application, given the large size of the human brain. Photobiomodulation has been reported to penetrate 20-30mm through a range of body tissues, from bone to brain. Hence, from a transcranial approach, photobiomodulation would only reach cortical layers of the brain (less than 10mm), but it would penetrate the retina.

Antibodies are generated in specialized cells called B cells. The pathway that generates these cells is highly complex, encompassing many precursor cell types. All of the early steps of this process occur in the bone marrow where dedicated precursor B cells are generated from hematopoietic stem cells. The aging process strongly impacts these early steps, with reduced numbers of precursor B cells and a decline in the developmental flow of these cells towards mature B cells that secrete antibodies. Importantly, this reduces the diversity of the antibody repertoire.

Since each B cell produces a different antibody, this is essentially a numbers game - the fewer B cell precursors you have, the less chance you have of producing a mature B cell with a good antibody match for any infection you may encounter. Precisely why the numbers of these precursors decline in the aged is not known. One theory is that this is linked to how genes are affected upon aging. Many genes code for proteins, the tools cells use for their function. Others code for regulatory molecules that control these proteins. The way genes are packaged and organized in the nucleus has a major impact on their expression, for example if they are switched on or off.

To test this theory, we decided to explore whether changes in the gene expression apparatus and genome organization in B cell precursors contribute to this decline. When we compared the expression of genes in B cell precursors from young and old mice, we found that aging affected only a relatively narrow set of genes. Significantly, several of these genes, including long, non-protein coding transcripts and small regulatory transcripts called microRNAs, participate in pathways that respond to nutritional status and link to growth and proliferation.

In particular, several key genes in the insulin-like growth factor (IGF) signaling pathway, a highly conserved regulatory pathway that is initiated by growth hormones in many cell types, were downregulated in the aged B cell precursor cells. We identified changes in genome organization that are linked to this downregulation. Our study suggests that relocation of genes between active and repressive nuclear environments might contribute to changes in gene expression upon aging. This is an unusual method of downregulation, since normally signalling pathways are modulated by fine tuning of cytoplasmic events, such as phosphorylation.