Here at CellAge we believe it is a great thing to be healthy, capable and enjoying life at any age. We also believe that you deserve to have safe and effective medical treatments to make this happen, and this is why we are working hard to create breakthrough therapies that will treat one of the key reasons for age-related disease: senescent cells. The current methods scientists use to identify and remove senescent cells have many limitations such as being too large to use in present gene therapies, being too imprecise in the range of cells affected, or simply being incomplete in cell targeting and removal. CellAge is building a new senescent cell targeting system that overcomes these limitations through the development of synthetic promoters, special DNA sequences that can regulate the activity and expression of genes.

In short, CellAge is going to develop synthetic promoters which are specific to senescent cells, as promoters that are currently being used to track senescent cells are simply not good enough to be used in therapies. The most prominently used p16 gene promoter has a number of limitations, for example. First, it is involved in cell cycle regulation, which poses a danger in targeting cells which are not dividing but not senescent either, such as quiescent stem cells. Second, organism-wide administration of gene therapy might at present be too dangerous. This means senescent cells only in specific organs might need to be targeted and the p16 promoter does not provide this level of specificity. Third, the p16 promoter is not active in all senescent cells. Thus, after therapies utilizing this promoter, a proportion of senescent cells would still remain. Moreover, the p16 promoter is relatively large, making it difficult to incorporate in present gene therapy vehicles. Lastly, to achieve the intended therapeutic effect the strength of a p16 promoter to drive therapeutic effect might not be high enough.

CellAge will be constructing a synthetic promoter which has a potential to overcome all of the mentioned limitations. With your help, we will be able to use same technology to develop tools and therapies for accurate senescent cell targeting. We have teamed up with leading synthetic biology company, Synpromics, to create two new exciting systems for detecting and removing senescent cells. A number of gene therapy companies, including uniQure, AGTC and Avalanche have already successfully used similar technology to target other kinds of cells; we are confident we can do the same for senescent cells.

Our primary goal with this project is the creation of SeneSENSE, a new system that can overcome the limitations of other approaches and provide researchers with an accurate way to detect senescent cells. We predict this system could also be used as a quality control step in the stem-cell therapy manufacturing process to make cell therapies safer! As we want to foster the development of senolytic therapies, we plan to give SeneSENSE to other scientists for free, to help them improve their results. We aim to have our cell detection system ready by Q4 2017 enabling researchers to benefit in the near future and helping to speed up progress.

We thought this would be a good time to not only thank you for the support you have given the Methuselah Foundation, but also to review the progress we made through your support over the past year. Much of what you'll read in this year in review letter is very late-breaking, and leads us to believe that 2017 will be a very important year in medical developments. 2016 took us a broad step closer to fulfilling our mission statement to "Make 90 the New 50, by 2030". Why can we say that? For starters, let's look at several achievements to date that made this year so successful:

Our Partnership with NASA

The White House Organ Summit was held this past June. At the formal press event we announced that we NASA had chosen to partner with us as leaders in the industry, along with the New Organ Alliance and CASIS to organize and administer a 500,000 prize to the first three teams who successfully create vascularized thick human tissue; the intended outcome is that it can be developed for therapeutic applications here both on earth (such as closing the gap in the organ shortage) and in deep space exploration. Why is this important? The outcome we are reaching for with the Vascular Tissue Challenge is in lockstep with our goal to bring "new parts for people" to the clinic - not just full organs for transplant, but all tissues: new skin, cartilage, nerve, vessels and bone. Microvascularization is the key barrier to allowing the explosion of progress towards "new parts for people". Methuselah is leading the way to pierce and destroy this barrier.

We have several updates on the NASA Vascular Tissue Challenge for you. Seven teams have now signed up to officially pursue the Vascular Tissue Challenge, and we co-chaired a session on the New Organ road-mapping work and Vascular tissue Challenge at the World Stem Cell Summit Dec 5-10. To aid in this endeavor, we completed a second road-mapping workshop with specific focus on overcoming the thick-tissue vascularization barrier. This was hosted at NASA Ames, Nov 9-10. We received participation from 100 leaders in the field, along with government representatives from NIH, NSF, VA, NASA, and DOD. We are pursuing the development of an expanded road-mapping Summit for 2017 that will be supported by NASA, NIH, NSF, CIRM, and other partners. We have made plans to expand the New Organ Alliance into an official Research Coordination Network with the NSF next year. This partnership with NASA and other medical pioneer organizations could lead to alleviating the suffering of those in need of organs, and add to the quality of life for millions in the future. It has us very excited!

Organovo

In September of this year our partner and portfolio company Organovo announced it had created the world's first ever 3-D architecturally correct human kidney tissue assays. What makes this a game changer? This development alone may cut off a decade or more of time, and save billions wasted in drug development. The ability to test viable human tissue will also make animal testing obsolete. The end result can also make much more effective drugs available much more quickly, and at a much lower cost. In addition, Organovo is continuing to build on these achievements by moving forward with work on a 3-D liver tissue "patch" for therapeutic use. These patches will help heal diseased kidneys and are on track to be developed in three to five years. We were also excited to announce, as part of our ongoing 3d Tissue Engineering University Printer Grant program, the UCSF bone organoid 3d Printer partnership in June 2016. This partnership is designed to research creation of new bones and cartilage. The Methuselah Foundation has also awarded a 3-D printer grant to Dr. Melissa Little of the Royal Children's Hospital in Melbourne, Australia, allowing her to collaborate with Organovo in this endeavor.

Organ Preservation Alliance

During 2016 the Organ Preservation Alliance was responsible for the launch of new cryopreservation and organ preservation initiatives, which were announced by the White House. Among them was a partnership with the American Society of Transplantation to launch a new branch of its organization devoted to advancing organ preservation and cryobanking. This resulted from an Organ Preservation Alliance-hosted roundtable on Capitol Hill that brought together almost 50 leaders from the American Heart Association, American Liver Foundation and other large stakeholder organizations. Also announced by the White House in 2016 was the upcoming Organ Banking Summit at Harvard, which brings together leading cryopreservation researchers and top researchers from other fields, prestigious journals, and transplant leaders. Other initiatives announced included 15 million in grants launched by the Dept. of Defense resulting from the Organ Preservation Alliance, a Breakthrough Ideas in Organ Banking hackathon, and a technology road-mapping program in partnership with New Organ, the American Society of Mechanical Engineers, and other organizations.

Leucadia

Our work through Leucadia Therapeutics has also yielded eye-opening developments this year. We continue to study the brain with a view towards alleviating the suffering of people and their loved ones when Alzheimer's disease begins to take its toll. We have undertaken deep examination of the cribriform plate, along with some otherwise overlooked approaches to studies of the brain and surrounding tissue and material. We believe we have originated approaches to treatment that appear to be profound. We are currently evaluating cribriform plates in Alzheimer's patients at a level of detail that has never been done before. This new level of detail that was only reached in late 2016 has opened doors to treatment that was unthinkable only a year ago. While we cannot elaborate at length on what or why we consider this approach "profound", we do want you to know we have a clear and definite path we are following. Our research is heading in a direction that could very well bring previously unmatched value to those suffering from Alzheimer's.

Oisin

Oisin Biotechnology made strong progress in recent months as we pursue a multi-pronged research in areas of longevity science. As a result of grants from Methuselah Foundation, Oisin has continued to pursue senescent cell ablation, and continues laying groundwork in eliminating senescent cells based on their gene expression. Research strongly implicates those cells in the aging phenotype, and removal has been shown to extend median survival and health span in mice. Oisin and our colleagues have greatly improved both the manufacturability and efficiency of our liposomal manufacturing process, which was a large, necessary step towards making the future therapy cost effective and affordable. We've also confirmed our findings of last year that our patent-pending approach effectively kills senescent cells in cell culture.

With support from Methuselah, SENS Research Foundation, and their longtime supporters, Oisin was able to secure sufficient funds for their continuing operations and thus avoid the need for venture capital - allowing it to focus on achieving Methuselah's strategy to "get the crud out". Oisin is also actively pursuing research in another very significant field that cannot be revealed in detail at this time of crucial testing and verification. However, our research on this particular project has exceeded all expectations. Once our verification work concludes, we will reveal this exciting work to all those of you who power the Methuselah Foundation. We are driven to get this to the clinic. What we are doing is not simply an academic pursuit! We are working hard to make a lasting and valuable difference in people's lives.

The Establishment of the Methuselah Fund

On December 2016, the Methuselah Foundation started a new initiative it expects will accelerate clinical delivery of mission relevant interventions. It is called the Methuselah Fund, or M Fund. Currently, the foundation believes that one of the fastest and most effective ways to achieve our mission is by investing in for-profit companies. We want to replicate and expand our successes via the M Fund, and we would love for you, our network, to be a part of this initiative.

Our Thanks to You

The Methuselah Foundation takes great pride and joy to inform you of all of these strides we are making in so many places. Through 2017 we will continue to think of the number of lives that may be saved. The amount of pain alleviated or even completely removed from families. It drives our researchers and associates to get up every day and push forward. Most importantly though, we never lose sight of the fact that it is you that makes our work possible. You continue to create the momentum for earth-changing progress. We want to thank all of you for your contributions to our Foundation that in turn empowers us to utilize the tools that will make a difference in so many people's lives, everywhere. We look forward to another rewarding year ahead with you, as we continue to push forward, creating a future that helps end suffering and changes the lives of millions.

Lysoclear is an enzyme therapy being developed for age-related macular degeneration (AMD) and Stargardt's macular degeneration. Age-related macular degeneration (AMD) is the leading cause of vision loss among people over the age of 50, affecting 20 million Americans. Stargardt's macular degeneration is an inherited conditions that robs children of their sight. Lysoclear shows promise as a highly targeted treatment for both conditions. Lysoclear has been extensively studied in buffer systems, cell culture models, and in vivo, and findings suggest that Lysoclear is safe and effecting at destroying toxic vitamin A aggregates (A2E) that may cause these diseases. Lysoclear is safe and effective at breaking down toxic A2E, removing up to 10% with each dose. Lysoclear selectively localizes to the lysosomes of retinal pigmented epithelial (RPE) cells where A2E accumulates, and destroys it.

Age-related macular degeneration (AMD) and Stargardt's macular degeneration (SMD) are thought to arise from the gradual loss of RPE cells of the macula, the area of the eye responsible for central vision. The accumulation of toxic vitamin A aggregates, including the bis-retinoid A2E, have been implicated in these diseases. Recent research suggests that A2E is capable of binding native lysosomal enzymes, inhibiting their function. As A2E accumulation reaches a critical threshold, lysosomal impairment leads to the accumulation of intracellular lipofuscin, extracellular drusen deposition, and eventually RPE cell death. Lysoclear is a recombinant enzyme product under development by Ichor Therapeutics that is able to selectively localize to the lysosomes of RPE cells where A2E accumulates, and destroy it.

Today, Ichor Therapeutics, a biotechnology company that focuses on developing drugs for age-related diseases, announced a series A offering to bring its Lysoclear product for age-related macular degeneration (AMD) and Stargardt's macular degeneration (SMD) through Phase I clinical trials. This product would be the first clinical candidate based on the SENS paradigm, pioneered by biomedical gerontologist Dr. Aubrey de Grey. AMD is the leading cause of vision loss among people over the age of 50. The underlying pathology of AMD is thought to be caused by the death of retinal pigmented epithelial (RPE) cells, which photoreceptors in the macula rely upon to survive. RPE cells assist photoreceptors in various metabolic roles, including the recycling of vitamin A, an essential component of the visual cycle. However, this is a leaky process, and trace by-products are formed that accumulate in the lysosomes of RPE cells. The most well studied of these by-products is A2E, a toxic compound which may play a causative role in AMD and SMD.

Although A2E accumulates gradually over the lifespan, it is generally not until later age that A2E reaches a threshold necessary to promote toxicity. At high concentrations, A2E promotes the formation of intracellular junk termed lipofuscin. RPE cells attempt to handle this accumulation by shuttling the junk out in the form of extracellular drusen. Eventually, the RPE cells choke on the garbage, and cell death accompanies complement activation, inflammation, and hypoxia. Multiple companies have developed drugs that successfully reduce the rate of A2E formation, but such interventions may be too late for symptomatic patients, who have already had the cascade kicked off.

In 2014, Ichor Therapeutics completed a material and technology transfer agreement for rights to concepts and research pioneered by SENS Research Foundation. In 2017 Ichor announced Lysoclear, a recombinant enzyme product that selectively localizes to the lysosomes of RPE cells where A2E accumulates, and destroys it. Ongoing studies suggest that LYSOCLEAR is safe and effective at targeting A2E, eliminating up to 10% with each dose. Ichor has opened a Series A funding round to support pre-clinical Investigational New Drug (IND) enabling studies and phase I human clinical trials for AMD and SMD.

Senescent cells have been recently shown to contribute causally to the aging process. Elimination of senescent cells by suicide gene-meditated ablation of p16Ink4a-expressing senescent cells in INK-ATTAC mice has led to improvements in healthspan and lifespan suggesting that senescent cells are drivers of aging. This has prompted the scientific community to identify new interventions to target senescence as a therapy against aging and age-related diseases. However, despite remarkable advances, the detection of senescent cells, particularly in tissues, is still a major challenge. There are several reasons, both of a biological and methodological nature, which have hindered the identification of specific markers able to determine whether a cell is senescent or not.

Firstly, while senescence is characterized by numerous changes in gene expression, very few of these differences are exclusive to senescent cells. Secondly, senescence is a kinetic, multifactorial process, with several phenotypic changes occurring at different time points following the initial cell cycle arrest. This could explain why aged tissues are highly heterogeneous, possibly containing cells at different stages of the senescent programme. Thirdly, senescent cells manifest the phenotype differently depending on the type of inducing stimuli or the cell type. Finally, recent data have highlighted that senescence may play different physiological roles in different contexts. For instance, an 'acute' type of senescence has been shown to play a beneficial role during processes such as development or tissue repair, while a 'chronic' type of senescence may contribute to aging and age-related disease. The recent realization that there may be different types of senescent cells in tissues has created an additional obstacle to the identification of a universal marker.

The detection of senescence-associated β-galactosidase (SA-β-Gal) activity at pH 6 is probably the most widely utilized method for identification of senescent cells. Nevertheless, there are major limitations to this method. Given the growing realization that senescence is a multifactorial process, a multimarker approach is being favoured by many researchers in the field. Examples of currently used markers are as follows: increased expression of cyclin kinase inhibitors p21 and p16 and absence of proliferation markers; telomere-associated DNA damage foci; senescence-associated heterochromatin foci; loss of lamin B1; senescence-associated distension of satellites (SADS); and expression of components of the SASP amongst several others. Nonetheless, there is also growing realization that many of these markers are not exclusive to all types of senescence and may only occur in specific cell types.

Lipofuscin is a nondegradable aggregate of oxidized lipids, covalently cross-linked proteins, oligosaccharides and transition metals which accumulate within lysosomes. Multiple studies indicate that lipofuscin accumulates in various tissues and species with age, particularly postmitotic tissues such as the brain and cardiac and skeletal muscle. However, lipofuscin has also been shown to accumulate during replicative senescence of human fibroblasts. Lipofuscin is autofluorescent and can be visualized using fluorescent microscopy; however, several other histochemical methods have been described based on lipid detection, such as staining using Sudan Black B (SBB) amongst others. Here, a structurally similar compound to SBB has been designed and coupled to biotin. Commercially available SBB contain numerous impurities which impact on staining quality and justified the need to synthesize a new analogue. The chemical coupling with biotin allows its detection using antibiotin antibodies and thereby increases its detection sensitivity. This method is versatile: it can be used in fresh, frozen cells and tissues, but also in fixed material. Furthermore, it can be identified in cells using both microscopy and flow cytometry.

While the authors have convincingly demonstrated that lipofuscin accumulation correlates with senescent markers in cell culture and that lipofuscin increases in tissues with age, future work should investigate more thoroughly whether and to what extent the lipofuscin signal overlaps with other established senescent markers. A separate question which arises from this work is whether lipofuscin accumulation is a mere consequence of the induction of the senescence programme or whether its accumulation contributes causally to the development of senescence.

Studying the phenomenon of cellular senescence has been hindered by the lack of senescence-specific markers. As such, detection of proteins informally associated with senescence accompanies the use of senescence-associated β-galactosidase as a collection of semiselective markers to monitor the presence of senescent cells. To identify novel biomarkers of senescence, we immunized BALB/c mice with senescent mouse lung fibroblasts and screened for antibodies that recognized senescence-associated cell-surface antigens by FACS analysis and a newly developed cell-based ELISA. The majority of antibodies that we isolated, cloned, and sequenced belonged to the IgM isotype of the innate immune system.

In-depth characterization of one of these monoclonal, polyreactive natural antibodies, the IgM clone 9H4, revealed its ability to recognize the intermediate filament vimentin. By using 9H4, we observed that senescent primary human fibroblasts express vimentin on their cell surface, and mass spectrometry analysis revealed a posttranslational modification on cysteine 328 (C328) by the oxidative adduct malondialdehyde (MDA). Moreover, elevated levels of secreted MDA-modified vimentin were detected in the plasma of aged senescence-accelerated mouse prone 8 mice, which are known to have deregulated reactive oxygen species metabolism and accelerated aging.

Based on these findings, we hypothesize that humoral innate immunity may recognize senescent cells by the presence of membrane-bound MDA-vimentin, presumably as part of a senescence eradication mechanism that may become impaired with age and result in senescent cell accumulation. Given the growing evidence that oxidized proteins are involved in the development of human disease, the detection and monitoring of secreted proteins like oxidized vimentin is certain to become a vital and noninvasive biomarker for monitoring age-related illnesses.

Adult muscle stem cells, originally called satellite cells (SCs), are essential for muscle repair and regeneration throughout life. Besides a gradual loss of mass and function, muscle aging is characterized by a decline in the repair capacity, which blunts muscle recovery after injury in elderly individuals. A major effort has been dedicated in recent years to deciphering the causes of SC dysfunction in aging animals, with the ultimate goal of rejuvenating old SCs and improving muscle function in elderly people. The emerging evidence indicates that the functional and numerical loss of SCs is a progressive process occurring throughout the lifetime of the organism. The long-lived quiescent SC accumulates many lesions caused by loss of homeostasis, metabolic alterations, and the aging environment. Although this process is gradual, it is accelerated in advanced old age to the extent that SCs become practically non-functional owing to senescence or apoptosis. In this context, disputes about which factors, intrinsic or extrinsic, are more dominant in dictating the fate of old SCs seem misplaced, and it is likely that both make important contributions to SC functional decline with aging.

A degree of success has been obtained in restoring the regenerative capacity of old muscle with both parabiosis experiments (extrinsic effect) and transplantation of ex vivo-rejuvenated SCs into old animals (intrinsic effect). The simplest explanation for these effects is the heterogeneous nature of SCs. Even in old age, the SC population includes a small percentage of functional SCs, with only limited accumulated damage that can be reversed still by extrinsic signaling factors or by ex vivo pharmacological inhibition of stress pathways such as p38 MAPK or JAK/STAT3. It is thus likely that the success of biochemical or genetic strategies applied to old SCs in transplantation experiments results from the proliferative amplification of a subset of highly regenerative cells. Alternatively, the health and fitness of old SCs could be increased by refueling "clean up" activities such as autophagy (which declines with aging) to eliminate damage, thus improving SC regenerative capacity after muscle injury and in transplantation procedures. Future interventions that could also be considered for combating age-related muscle regenerative decline may utilize the restoration of SC-niche interactions via the delivery of bioengineered molecules.

The key finding that the SC pool enters a state of irreversible senescence at a geriatric age implies that any treatment to rejuvenate endogenous stem cells should be implemented before this point of no return. It is also important to consider the link between SC regenerative potential and quiescence. It is generally well accepted that the more quiescent a stem cell is, the more regenerative capacity it has. It has also become clear that somatic stem cell populations are heterogeneous, with cells showing differing levels of quiescence. Highly quiescent subpopulations probably change with aging to become less quiescent and therefore of reduced regenerative capacity. SC heterogeneity should therefore be further investigated, with the aim of deciphering the molecular basis of quiescence. Understanding the quiescent state will allow early intervention aimed at preserving the highly regenerative quiescent subpopulations throughout life.

Likewise, strategies directed towards the expansion of relevant subpopulations of resident progenitor cells in the SC niche may be envisioned for reversing the age-associated muscle regenerative loss. Another unresolved issue is the interaction among the various events contributing to the loss of SC regenerative potential with aging. Research needs to focus on determining which events are causative and which are consequential. For example, DNA damage may induce the loss of baseline autophagy flux in old SCs, or alternatively DNA damage may be the consequence of oxidative stress resulting from the loss of autophagy flux. Defining the hierarchy of events leading to SC deterioration will enable the targeting of upstream events in order to achieve more efficient rejuvenation of SCs. Last but not least, in a low-turnover tissue like muscle, much of the damage to the quiescent SC is the result of the gradual decline (aging) of the niche composition and the systemic system. Future efforts to rejuvenate the regenerative potential of SCs should thus adopt a holistic view of the SC and its supportive environment.

Preventing pathological conditions caused by aging, including cancer, osteoporosis, sarcopenia, and cognitive disorders, is one of the most important issues for human health, especially in societies with large aging populations. Although aging, defined by functional decline of cells/organs or accumulation of cell/organ damage, is one of the most recognizable biological characteristics in all creatures, our understanding of mechanisms underlying the aging process remains incomplete. The primary cause of functional declines occurring along with aging is considered to be the exhaustion of stem cell functions in their corresponding tissues. Stem cell exhaustion is induced by several mechanisms, including accumulation of DNA damage and increased expression of cell cycle inhibitory factors, such as p16 and p21.

Meanwhile, aging at cellular, tissue, organ and organismic levels has been reversed by exposing tissues from old animals to a young environment. Recent studies have suggested that stem cell rejuvenation could reverse organismal aging phenotypes, and that this could be achieved by inhibiting fibroblast growth factor 2, mammalian target of rapamycin (mTOR) complex 1, guanosine triphosphatase and cell division control protein 42. Several additional experiments, such as cross-age transplantation and heterochronic parabiosis, have revealed that some factors in the young systemic milieu can rejuvenate declined thymus gland function, as well as neural and muscle stem cell functions, in samples derived from elderly donors. Furthermore, heterochronic parabiosis experiments have also shown strong inhibition of young tissue stem cells by the aged systemic milieu or old serum.

Although cumulative cellular "intrinsic changes", such as DNA damage, oxidative damage, increased expression of cell cycle inhibitors and mitochondria dysfunction, have been considered likely culprits for the tissue decline observed with aging, cellular rejuvenation induced by young systemic milieu would have been impossible if "intrinsic changes" were the only cause of cellular aging. Therefore, these so-called "causes of aging" should be more properly regarded as effects of aging (i.e., these processes are not causes, but rather consequences of aging), the result of cellular decisions often defined by responses to "extrinsic stimuli". Here some questions arise: If aging at the cellular level were reversed, would it lead to the rejuvenation of the animal at an organismic level? Would it result in prevention of aging and, eventually, life extension?

Hypertension is very common, especially in older adults, and it contributes to a number of other cardiovascular disorders. Although a variety of therapeutic interventions are available for this condition, none of them are specific or long-lasting, and they can all cause side effects, which decrease adherence to treatment. Researchers discovered that increased expression of thioredoxin, a protein that scavenges free radicals and restores proteins damaged by oxidation, reduced hypertension in mice. Injection of recombinant human thioredoxin also reduced hypertension in mouse models, and its protective effects lasted for weeks, suggesting that it may be possible to adapt this approach for chronic treatment of human patients.

The incidence of high blood pressure with advancing age is notably high, and it is an independent prognostic factor for the onset or progression of a variety of cardiovascular disorders. Although age-related hypertension is an established phenomenon, current treatments are only palliative but not curative. Thus, there is a critical need for a curative therapy against age-related hypertension, which could greatly decrease the incidence of cardiovascular disorders. We show that overexpression of human thioredoxin (TRX), a redox protein, in mice prevents age-related hypertension. Further, injection of recombinant human TRX (rhTRX) for three consecutive days reversed hypertension in aged wild-type mice, and this effect lasted for at least 20 days. Arteries of wild-type mice injected with rhTRX or mice with TRX overexpression exhibited decreased arterial stiffness, greater endothelium-dependent relaxation, increased nitric oxide production, and decreased superoxide anion generation compared to either saline-injected aged wild-type mice or mice with TRX deficiency. Our study demonstrates a potential translational role of rhTRX in reversing age-related hypertension with long-lasting efficacy.

A small but clinically important trial of a new ultra-low dose four-in-one pill to treat high blood pressure has produced remarkable results. Every patient on the pilot trial saw their blood pressure levels drop to normal levels in just four weeks. Researchers said the results were exciting but larger trials were needed to see if these high rates could be maintained and repeated. "Most people receive one medicine at a normal dose but that only controls blood pressure about half the time. In this small trial blood pressure control was achieved for everyone. Trials will now test whether this can be repeated and maintained long-term. Minimising side effects is important for long-term treatments - we didn't see any issues in this trial, as you would hope with very low dose therapy, but this is the area where more long-term research is most needed. We know that high blood pressure is a precursor to stroke, diabetes and heart attack. The need for even lower blood pressure levels has been widely accepted in the last few years. So this could be an incredibly important step in helping to reduce the burden of disease globally."

Over four weeks 18 patients were either given a quadpill - a single capsule containing four of the most commonly used blood pressure-lowering drugs each at a quarter dose - or a placebo. This was then repeated for a further four weeks with the patients swapping their course of treatment. Blood pressure levels were measured hourly over a 24 hour period at the end of each treatment, allowing researchers to significantly reduce the amount of patients normally required in a clinical trial. 100 per cent of patients on trial saw their blood levels drop below 140 over 90. Just 33 per cent of patients on the placebo achieved this rate. None of the patients experienced side effects commonly associated with hypertension lowering drugs, which can vary from swollen ankles to kidney abnormalities depending on the type of class of the drug. "What makes these result every more exciting is that these four blood pressure medications are already in use. We are increasingly finding there are opportunities to treat many commons diseases hiding in plain sight. This ultimately means we will be able to deliver life changing medications much more quickly, and more affordably."

Modern health and medicine have all but eradicated the poxes and plagues that fixed the life expectancy of a person in the 19th century at 40 years old, but despite long and expensive struggles like "The War on Cancer" and over a hundred clinical trials for Alzheimer's treatments, our attempts to control the diseases of aging have borne little fruit. In the last thirty years, our understanding of the underlying pathology of Alzheimer's disease has deepened, yet billions invested in research have not significantly slowed the course of the disease. Most existing treatments for cancer require swift detection, are extremely invasive and expensive, and cause debilitating side effects. And our defenses against heart disease, stroke, and general frailty remain, at best, crude.

Up to now, most approaches have focused on acute treatment of disease, waiting until a patient has obvious or life-threatening symptoms before intervening. The central tenet of geroscience, however, is that the molecular and cellular damage that leads to the diseases of aging begins long before people appear sick. Our risk of getting these diseases peaks after sixty years of age, but the incremental buildup of damage starts in our twenties or thirties. The geroscience approach aims to target the molecular processes that underpin aging here, and fix them at their roots, stopping aging before it starts.

But what are these processes? What are the threads linking all of the ails of aging together to slowly break down our bodies and minds? Over several decades, researchers have unraveled this mystery to find nine interwoven "hallmarks of aging": genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Already interventions targeting one or more of these factors are being developed, from small molecule drugs to genetic alterations, and over fifty have been found to extend lifespan and healthspan in mice, with more being discovered every year.

In the past few years, a rapidly growing industry has sprung up around the geroscience approach, with both companies producing individual technologies like UNITY Biotechnology, and tech giants like Google and Facebook making broader moves into the space. Google's Calico, an independent R&D biotech company partnering with AbbVie and numerous academic institutes, was founded in 2013 to promote "health, well-being, and longevity", and in 2016 Mark Zuckerberg pledged 3 billion to Chan Zuckerberg Science with the goal of curing or preventing all disease by 2100. In addition to these large investments into basic research, more commercially focused endeavors like Genentech and Eli Lilly's Alzheimer's trials and GenSight's efforts to replace defective mitochondrial genes have been popping up as well. We are on the verge of a paradigm shift in how we treat the diseases of aging. The first medicines to make us live longer and healthier lives already exist, and massive investments are catalyzing the creation of many more. We are poised to be either the first generation to live for over a century, or the last generation not to. We've created Geroscience to share our enthusiasm for this space, and to cultivate a source of accessible science and realistic discourse.

I am a first year Biostatistics PhD student at the University of Colorado. Listening to J. D. Vance's Hillbilly Elegy reminds me of my roots growing up along US 23 in Eastern Kentucky. So who am I? I'm the guy who fixed your air conditioner, roofed your house, changed the spark plugs in your car's engine, worked the production line in a food factory, defended your country during war, waited your table at your favorite restaurant and even washed your dishes after you were done. Now, I want to join the united front to end the most widespread cause of human suffering - aging. It was a very serendipitous moment that inspired me to read Aubrey de Grey's book Ending Aging in 2008. I was living in Louisville, Kentucky and spent my free time from working at a White Castle frozen hamburger factory hanging out in a local coffee shop. Adjacent to that coffee shop was Carmichael's, a local, independent bookstore. That day I went straight to my favorite section, Science and Math. And what I found was not just a book, but hope.

Ending Aging spoke to me. Dr. de Grey told us not to accept humanity as the limits of our DNA. Challenge the status quo and possibly discover how great we may become. Every generation believes that they can do better than their parent's generation. Until one day that generation wanes into the symptoms of aging. Great men and women lose their dignity because a care worker or family member has to perform what once were remedial tasks for them. But the indecencies attached to the aged bodies of our loved ones wasn't what sold me on SENS. Dr. de Grey's analogy of maintaining an antique car caught my attention early in the reading of his book. This was a direct appeal to my inner mechanic. I read during my 30-minute lunch breaks at the White Castle hamburger factory. Separating six burgers into three sets of two on a transfer belt and sliding them into a moving slot to be wrapped in cellophane at a rate of one pair per second, I would let my mind wander into another world. What are the seven categories of damage that would need to be reversed? Is this list all encompassing? Doing repairs may be easier than changing metabolic pathways, but would it even be possible. What would a society be like if age-related illnesses were eliminated? I was onboard and wanted to be a part of the next step in human improvement.

There was this moment where I decided to stop spoon feeding my wife the ideas of SENS and unleashed all my thoughts on her at once. When I proposed the idea of me becoming a researcher, it became apparent that working 60+ hours a week at a factory and having two kids under the age of three would not be an ideal time to go back to school. Hence, we waited. I obtained a horizontal promotion as a service technician for the restaurant division. I still read cellular biology books in my spare time and googled Aubrey de Grey more than once a week to see his progress. Then, an opportunity presented itself to me. My neighbor found it interesting that this mechanic neighbor of his was reading biology textbooks when he wasn't being called out in the middle of the night to fix a freezer. He asked me if I would be interested in a career in the medical field and said he could get me an interview but that was it. I had to submit a resume before my interview. There was nothing in my past that would qualify me for this job. Nonetheless, my new boss hired me and said they could teach me what I didn't know.

Later, with great support from family and friends, I finished two degrees, BS Pure Mathematics and MS Biostatistics. Currently, I am focusing on my studies as a first year PhD student in Biostatistics in the beautiful state of Colorado. The teaching staff here is incredible. They are pushing me to be the best I can be while still providing me some space to allow my family and myself to adapt to our new environment. I am taking a course on genomics which has a strong emphasis on the technology of measuring gene expression and various sequencing platforms. I just published my first paper in Breast Cancer Treatment and Research as a primary author. After my doctorate, I would like to work on a research team in a biotech company. I am open to academic research and wouldn't discount any opportunity. My desire is to spend my days working with innovative people to solve the mysteries of controlling aging. I don't care what platform provides that for me.

Recent research offers one glimpse into how cutting calories impacts aging inside a cell. The researchers found that when ribosomes - the cell's protein makers - slow down, the aging process slows too. The decreased speed lowers production but gives ribosomes extra time to repair themselves. "The ribosome is a very complex machine, sort of like your car, and it periodically needs maintenance to replace the parts that wear out the fastest. When tires wear out, you don't throw the whole car away and buy new ones. It's cheaper to replace the tires." So what causes ribosome production to slow down in the first place? At least for mice: reduced calorie consumption.

Researchers observed two groups of mice. One group had unlimited access to food while the other was restricted to consume 35 percent fewer calories, though still receiving all the necessary nutrients for survival. "When you restrict calorie consumption, there's almost a linear increase in lifespan. We inferred that the restriction caused real biochemical changes that slowed down the rate of aging." The team isn't the first to make the connection between cut calories and lifespan, but they were the first to show that general protein synthesis slows down and to recognize the ribosome's role in facilitating those youth-extending biochemical changes. "The calorie-restricted mice are more energetic and suffered fewer diseases. And it's not just that they're living longer, but because they're better at maintaining their bodies, they're younger for longer as well."

Ribosomes, like cars, are expensive and important - they use 10-20 percent of the cell's total energy to build all the proteins necessary for the cell to operate. Because of this, it's impractical to destroy an entire ribosome when it starts to malfunction. But repairing individual parts of the ribosome on a regular basis enables ribosomes to continue producing high-quality proteins for longer than they would otherwise. This top-quality production in turn keeps cells and the entire body functioning well.

Neurodegenerative diseases like Alzheimer's and Parkinson's may be linked to defective brain cells disposing toxic proteins that make neighboring cells sick. Researchers found that while healthy neurons should be able to sort out and rid brain cells of toxic proteins and damaged cell structures without causing problems, this does not always occur. These findings could have major implications for neurological disease in humans and could possibly be the way that disease can spread in the brain. "Normally the process of throwing out this trash would be a good thing. We think that there might be a mismanagement of this very important process that is supposed to protect neurons but, instead, is doing harm to neighbor cells."

Scientists have understood how the process of eliminating toxic cellular substances works internally within the cell, comparing it to a garbage disposal getting rid of waste, but they did not know how cells released the garbage externally. "What we found out could be compared to a person collecting trash and putting it outside for garbage day. They actively select and sort the trash from the good stuff, but if it's not picked up, the garbage can cause real problems."

Working with the transparent roundworm C. elegans, which are similar in molecular form, function, and genetics to those of humans, researchers discovered that the worms - which have a lifespan of about three weeks - had an external garbage removal mechanism and were disposing these toxic proteins outside the cell as well. The team realized what was occurring when they observed a small cloud-like, bright blob forming outside of the cell in some of the worms. Over two years, they counted and monitored their production and degradation in single still images until finally they caught one in mid-formation. Roundworms engineered to produce human disease proteins associated with Huntington's disease and Alzheimer's threw out more trash consisting of these neurodegenerative toxic materials. While neighboring cells degraded some of the material, more distant cells scavenged other portions of the diseased proteins.

>From an evolutionary perspective, aging has been difficult to understand. Natural selection increases organismal fitness, and yet aging, which clearly decreases fitness, is not only observed, but also appears to be nearly universal within multicellular (and even some single-celled) organisms. To address this dilemma, it was proposed that aging occurs and is fixed in populations because alleles that have deleterious effects in old age benefit growth, survival, and reproduction in youth. This theory is called antagonistic pleiotropy (AP) theory. In this view, aging occurs because alleles that in the short term are beneficial in solving problems in growth and reproduction serve to exacerbate the problem in the long run. Therefore, aging can be viewed as a form of death spiral. A death spiral, also known as a vicious circle, is a specific form of positive feedback in which steps taken to handle a particular problem, while successful in the short term, exacerbate the problem in the long term.

If this premise is accepted, the next step is to identify the alleles that mediate AP, understand the nature of these alleles, how they might exert AP, and finally identify and define the critical cellular processes affected by AP. Although genes of the insulin signaling pathway likely participate in AP, the insulin-regulated cellular correlates of AP have not been identified. The mitochondrial quality control process called mitochondrial autophagy (mitophagy), which is inhibited by insulin signaling, might represent a cellular correlate of AP. In this view, rapidly growing cells are limited by ATP production; these cells thus actively inhibit mitophagy to maximize mitochondrial ATP production and compete successfully for scarce nutrients. This process maximizes early growth and reproduction, but by permitting the persistence of damaged mitochondria with mitochondrial DNA mutations, becomes detrimental in the longer term.

I suggest that as mitochondrial ATP output drops, cells respond by further inhibiting mitophagy, leading to a further decrease in ATP output in a classic death spiral. I suggest that this increasing ATP deficit is communicated by progressive increases in mitochondrial reactive oxygen species (ROS) generation, which signals inhibition of mitophagy via ROS-dependent activation of insulin signaling. This hypothesis clarifies a role for ROS in aging, explains why insulin signaling inhibits autophagy, and why cells become progressively more oxidized during aging with increased levels of insulin signaling and decreased levels of autophagy. I suggest that the mitochondrial death spiral is not an error in cell physiology but rather a rational approach to the problem of enabling successful growth and reproduction in a competitive world of scarce nutrients.

Biologists have known for decades that enduring a short period of mild stress makes simple organisms and human cells better able to survive additional stress later in life. Now, scientists have found that a cellular process called autophagy is critically involved in providing the benefits of temporary stress. Autophagy is a means of recycling cells' old, broken, or unneeded parts so that their components can be re-used to make new molecules or be burned for energy. The process had previously been linked to longevity. The new results suggest that long life and stress resistance are connected at the cellular level.

The researchers incubated C. elegans worms at 36 °C, significantly above the temperature they are usually kept at in the laboratory, for one hour. After this short heat exposure - a mild form of stress that improves the organism's survival - autophagy rates increased throughout the worms' tissues. When they exposed these heat-primed worms to another, longer heat shock a few days later, worms that were deficient in autophagy failed to benefit from the initial mild heat shock, as observed in heat-primed worms with intact autophagy.

The researchers reasoned that a mild heat stress might also improve the worms' ability to handle another condition that worsens with age - buildup of aggregated proteins, which is stressful for cells. To test this hypothesis, they used worms that model Huntington's disease, a fatal inherited disorder caused by neuronal proteins that start to stick together into big clumps as patients age, leading to degeneration throughout the brain. Exposing worms that make similar sticky proteins in different tissues to a mild heat shock reduced the number of protein aggregates, suggesting that a limited amount of heat stress can reduce toxic protein aggregation. "Our finding that brief heat exposure helps alleviate protein aggregation is exciting because it could lead to new approaches to slow the advance of neurodegenerative diseases such as Huntington's. This research raises many exciting questions. For example, how does induction of autophagy by a mild heat stress early on make cells better able to survive heat later - what's the cellular memory? There's a lot to follow up on."

A new study finds that providing the body with a temporary, specifically formulated fasting mimicking diet (FMD) called ProLon causes cellular changes normally generated by several days of consecutive water-only fasting and may increase health and lifespan by partially turning back the aging clock. After animal results showing that this FMD reduces incidence of cancer and inflammatory diseases and extends lifespan, researchers have now published the results of a 100-participant randomized Phase II clinical trial demonstrating that ProLon targets the aging process and reduces risk factors for age related diseases such as diabetes, cancer, and cardiovascular disease in humans. These effects are believed to be caused by an increase in stem cell number and regeneration.

Pre-clinical studies demonstrated that ProLon provides the body with the necessary macro and micronutrients while keeping it in a fasting mode and activates stem cell-based regeneration in multiple organs and systems. ProLon is perhaps the first success story in a new but rapidly developing nutri-technology field. The understanding of the molecular connections between specific food components and genes that regulate aging and regeneration allows food to be used to promote cellular changes that are safe but more coordinated than those caused by drugs.

Researchers tested the effects of three monthly ProLon cycles on metabolic markers and risk factors associated with aging and age-related diseases. Each ProLon cycle lasts five consecutive days and does not require alteration to lifestyle during the remaining days of the month. Findings in humans were consistent with mouse studies showing a spike in circulating stem cells and delay in biological aging by promoting regeneration in multiple systems. Body weight, BMI, total body fat, trunk fat, waist circumference, systolic and diastolic blood pressure, cholesterol, insulin-like growth factor 1 (IGF-1), and C-Reactive Protein (a marker of inflammation) were significantly reduced, particularly in participants at risk for diseases, while relative lean body mass (muscle and bone mass) was increased. Low levels of IGF-1 are associated with a lower risk of cancer and diabetes. No serious adverse effects were reported.

It has been long established that aging is the greatest risk factor for a range of diseases. Caloric restriction (CR) is a dietary intervention that delays aging and extends the period of health in diverse species. One of the hallmarks of caloric restriction is the marked reduction in adiposity, a consequence that may be important in the mechanisms of CR given the endocrine function of adipose tissue. Adipokines and lipokines secreted from white adipose tissue impact peripheral tissue fuel utilization and the balance of energy generation from lipid or carbohydrate sources. However, it is unclear what effect aging has on adipose tissue metabolic integrity and how that relates to secretion of systemic regulatory factors. Prior studies of gene expression in adipose tissues from old rats and adult mice show that CR induces expression of genes involved in multiple aspects of metabolism. A further difference includes the increased circulating levels of the adipose tissue-derived peptide hormone adiponectin with long-term stringent (40%) CR.

In order to understand whether age-related changes in adiposity are associated with a change in adipose tissue function, we undertook a cross-sectional mouse study focusing on adipose tissue metabolism and circulating levels of adipose tissue-derived signaling molecules. To capture the trajectory of aging, the study involved adult, late-middle-aged, and advanced-aged C3B6F1 hybrid mice. Parallel groups of mice on modest (16%) CR taken at each age served to uncover aspects of adipose tissue aging that were responsive to delayed aging. We investigated the relationship between adiposity, adipocyte size, and adiponectin levels at three age groups of mice on control or CR diets. We determined whether differences with age and diet were associated with changes in factors downstream of adiponectin and factors that connect with adiponectin signaling including NAD metabolism. To investigate differences in adipose tissue lipid metabolism, we profiled serum lipids including free fatty acids that are derived from adipose tissue. The goal of these studies was to determine how age and CR impacted adipose tissue function beyond simple differences in adiposity and whether relationships between adipocyte size and secretory profiles were sustained with age or altered with CR.

Adiposity and the relationship between adiposity and circulating levels of the adipose-derived peptide hormone adiponectin were age-sensitive. CR impacted adiposity but only levels of the high molecular weight isoform of adiponectin responded to CR. Activators of metabolism including PGC-1a, SIRT1, and NAMPT were differentially expressed with CR in adipose tissues. Although age had a significant impact on NAD metabolism, the impact of CR was subtle and related to differences in reliance on oxidative metabolism. The impact of age on circulating lipids was limited to composition of circulating phospholipids. In contrast, the impact of CR was detected in all lipid classes regardless of age, suggesting a profound difference in lipid metabolism. These data demonstrate that aspects of adipose tissue metabolism are life phase specific and that CR is associated with a distinct metabolic state, suggesting that adipose tissue signaling presents a suitable target for interventions to delay aging.