Fight Aging! Newsletter, October 9th 2017

To coincide with our initiatives for Longevity Month, we are happy to announce some exciting updates for the MouseAge campaign to create a visual biomarker for mouse aging and speed the pace of longevity-focused mouse trials. The A.I. engineers on the team , with the support of Youth Laboratories, have decided to volunteer their assistance, pledging to donate their time in developing the machine learning algorithm and software engineering components of this project. This will effectively allow all goals on the crowdfunding campaign to be reduced by 15,000, and the initial goal will now stand at 15,000.

Together with a coalition of generous supporters LEAF has built up a pool of matching funds to support the campaign. This means that all donations will be doubled up until the new initial goal of 15,000 is reached. 1,000 in matching funds will be released for every 1,000 donated, so together we can move very quickly to support this important project!

Over the past few years there has been a tradition of longevity researchers and activists around the world organizing events on or around October 1 - the UN International Day of Older Persons, or Longevity Day. This year we want to continue this tradition by doing something special, making a video to showcase you, our community, as it is only with your outstanding help that we have been able to accomplish so much in such a short period of time. So now it is your turn to tell us your story, and let the world know why you care about research to end the diseases of aging. We will be accepting videos all through the month of October, Longevity Month, and we are also extending the MouseAge campaign to match this timeline. With these videos we will create a compilation to be unveiled on Giving Tuesday , November 28, 2017.

Proteostasis is necessary for most cellular functions, such as genetic replication, catalysis of metabolic reactions, and the immune response. Impairments in proteostasis can lead to toxic aggregations and accumulation of unwanted proteins resulting in cellular dysfunction. The maintenance of tissue homeostasis and the regenerative capacity after an injury depends on tissue-specific stem cells. The elucidation of the hallmarks of aging identified the impairment of protein homeostasis and stem cell exhaustion as major processes involved in the decline of the regenerative potential capacity linked to the accumulation of age-associated damage.

Autophagy is a highly conserved catabolic process, essential for this protein quality control, where intracellular components are delivered to lysosomes for self-degradation. There are three different types of autophagy depending on the signals that induce the pathway, and the mechanism by which the cargo reaches the lysosome: macro-autophagy (MA), micro-autophagy, and chaperone-mediated autophagy (CMA). In particular, MA is involved in recycling long-lived proteins and cytoplasmic organelles. This process implies the incorporation of proteins, organelles, and cytoplasm in a structure called the autophagosome, which once formed fuses with the lysosome to form autolysosomes and then releasing its content in the lysosomal lumen where it is degraded via acid hydrolases. Autophagy basal levels are very low under normal conditions, and they are activated in response to stress and extracellular cues.

Aging results from the accumulation of cellular damage promoted by chronic stresses of small magnitude. Therefore, being a sensor of stress, autophagy has been linked to aging. Several studies have described a decline in autophagy activity as well as expression of autophagy genes such as Atg1, Atg5, Atg6, Atg7, Atg8, and Atg12 in response to aging in several animal models and human tissues. The majority of these works have focused on MA, the most studied form of autophagic process, but there have also been studies showing a decline in CMA, particularly in the liver and the central nervous system, which have been linked to decreased function in these organs. Longevity studies with gain and loss of autophagy genes in animal models such as yeast, C. elegans, Drosophila and mice, support a direct role for autophagy in longevity, aging and development of age-associated pathologies. This has encouraged the scientific community to identify the precise role and molecular mechanisms of autophagy in aging, as targeting autophagy could be a novel therapy against aging and age-related diseases.

How autophagy decreases with age remains unclear and under intense investigation. Recent works carried on aged muscle stem cells (MSC) and hematopoietic stem cells (HSC) have revealed the impairment of MA in stem cell activity with aging. Moreover, these studies have confirmed that correct functioning of MA is necessary to maintain the appropriate blood system and muscle development and to allow adult stem cell to survive under metabolic stress. These studies suggest that MSC and HSC lose their regenerative abilities when they reach an advanced age and that autophagy is deficient in the old stem cell population. In a recent work, it was found that approximately 30% of aged HSCs exhibited high autophagy levels, maintaining a low metabolic state and strong long-term regeneration potential similar to young HSCs. However, the remaining population of aged HSCs showed loss of autophagy, which causes activated metabolic state, accelerated myeloid differentiation, and impaired HSCs self-renewal activity and regenerative potential.

These studies confirm that autophagy maintains stemness in MSC and HSCs; however, the maintenance of this feature seems to be different in each niche. Whether these results can be translated to other stem cell niches will be determined in the future. In addition, it will also be important to elucidate whether CMA or micro-autophagy play any role in stem cell aging. In summary, there is a requirement of correct autophagy activity for stem cell function, and the pharmacological restoration of autophagy is postulated as a novel strategy to boost stem cell activity for regenerative medicine and aging.

Human cells have complicated ways to protect themselves from becoming cancerous. One way is to force "premature aging" via senescence, a process that induces cells to stop growing. Although senescence suppresses cancer, which is the good side of this physiological balance, there is also a dark side. Senescence is associated with normal aging, and senescent cells accumulate in aged tissues. This accumulation impairs healthy tissue by triggering hyper-inflammation. This overdrive eventually contributes to age-related diseases including cancer, heart disease, and neurodegeneration. The overall idea for future therapy is to make a small molecule that could stop the dark side of senescence to treat age-related diseases, especially those related to chronic inflammation.

"Chromatin - structures in the cell nucleus in which genes reside - is traditionally viewed as a cell component that stays put in the nucleus to regulate gene expression. We discovered misplaced chromatin fragments outside the nucleus that pinch off from the nuclei of senescent cells." This wayward chromatin activates a DNA-sensing pathway called cGAS-STING, a mechanism based outside the nucleus best known for restraining microbial infection, such as by bacteria or viruses. In the case of senescence and aging, the body's own chromatin leaking outside of the nucleus is read by cells as a "danger signal" akin to a microbial infection. The misplaced fragments and the cell's reaction to them eventually lead to inflammation. "While short-term inflammation can help stop cancer from starting, the problem is that long-term, chronic inflammation can lead to tissue destruction, aging, and even, paradoxically, can help cancer to grow and spread."

Mice without an active alarm pathway that have been exposed to a cancer-inducing stress do not call the immune-system for help. This causes problems because damaged cells give rise to tumors in the impaired mice. However, when normal mice are exposed to stressors that induce aging, the build-up of senescent cells stimulates a continual call for immune cells, leading to chronic inflammation, which ultimately causes tissue damage and premature aging. Months after receiving irradiation stress, normal mice with an active alarm system showed massive graying of their fur, a sign of aging in mammals, just like humans show grey hair in old age. By sharp contrast, mice without the alarm system still had their black fur after irradiation. The researchers believe that finding molecules to target the always-on inflammatory pathway may hold promise in treating chronic inflammation associated with numerous diseases, especially those of aging, such as arthritis, arteriosclerosis, neurodegeneration, obesity, and possibly even hair graying and loss.

Chromatin is traditionally viewed as a nuclear entity that regulates gene expression and silencing. However, we recently discovered the presence of cytoplasmic chromatin fragments that pinch off from intact nuclei of primary cells during senescence, a form of terminal cell-cycle arrest associated with pro-inflammatory responses. The functional significance of chromatin in the cytoplasm is unclear.

Here we show that cytoplasmic chromatin activates the innate immunity cytosolic DNA-sensing cGAS-STING (cyclic GMP-AMP synthase linked to stimulator of interferon genes) pathway, leading both to short-term inflammation to restrain activated oncogenes and to chronic inflammation that associates with tissue destruction and cancer. The cytoplasmic chromatin-cGAS-STING pathway promotes the senescence-associated secretory phenotype in primary human cells and in mice.

Mice deficient in STING show impaired immuno-surveillance of oncogenic RAS and reduced tissue inflammation upon ionizing radiation. Furthermore, this pathway is activated in cancer cells, and correlates with pro-inflammatory gene expression in human cancers. Overall, our findings indicate that genomic DNA serves as a reservoir to initiate a pro-inflammatory pathway in the cytoplasm in senescence and cancer. Targeting the cytoplasmic chromatin-mediated pathway may hold promise in treating inflammation-related disorders.

Given the rapid aging of the world population and the accompanying rise of aging-related diseases and disabilities, the task of increasing the healthy and productive period of life becomes an urgent global priority. It is becoming increasingly clear that in order to accomplish this purpose, there is an urgent need for effective therapies against degenerative aging processes underlying major aging related diseases, including heart disease, neurodegenerative diseases, type 2 diabetes, cancer, pulmonary obstructive diseases.

One facilitating possibility may be to recognize the degenerative aging process itself as a medical problem to be addressed. Such recognition may accelerate research, development and distribution in several aspects: 1) the general public will be encouraged to actively demand and intelligently apply aging-ameliorating, preventive therapies; 2) the pharmaceutical and medical technology industry will be encouraged to develop and bring effective aging-ameliorating therapies and technologies to the market; 3) health insurance, life insurance and healthcare systems will obtain a new area for reimbursement practices, which will encourage them and their subjects to promote healthy longevity; 4) regulators and policy makers will be encouraged to prioritize and increase investments of public funds into aging-related research and development; 5) scientists and students will be encouraged to tackle a scientifically exciting and practically vital problem of aging.

Yet, in order for the degenerative aging process to be recognized as a diagnosable and treatable medical condition and therefore an indication for research, development and treatment, a necessary condition appears to be the development of evidence-based diagnostic criteria and definitions for degenerative aging. Such commonly accepted criteria and definitions are currently lacking. Yet without such scientifically grounded and clinically applicable criteria, the discussions about "ameliorating" or even "curing" degenerative aging processes will be mere slogans. Such criteria are explicitly requested by major regulatory frameworks, such as the International Classification of Diseases (ICD), the Global Strategy and Action Plan on Ageing and Health (GSAP), the European Medicines Agency (EMA), the US Food and Drug Administration (FDA). Nonetheless, nobody has yet done the necessary work of devising such criteria.

"Senility," tantamount to degenerative aging, is already a part of the current ICD-10 listing. In the draft ICD-11 version (to be finalized by 2018), the code MJ43 refers to "Old age," synonymous with "senescence" and "senile debility." The nearly 40 associated index terms in the ICD-11 draft also include "ageing" itself, "senility," "senile degeneration," "senile decay," "frailty of old age," and others. Still, the current definitions, such as "senility," seem to be rather deficient in terms of their clinical utility. This may be the reason why "senility" has been commonly considered a garbage code, e.g. in the Global Burden of Disease (GBD) studies. The reason "senility" has been considered a garbage code is likely because there have been no reliable, clinically applicable and scientifically grounded criteria for diagnosis of "senility" or of "senile degeneration." Consequently, there could be no official case finding lists. Hence, in order to successfully use this code in practice, it appears to be necessary to be able to develop formal and measurable, biomarkers-based and function-based diagnostic criteria for "senility" or "senile degeneration," as well as measurable agreed means to test the effectiveness of interventions against this condition.

Researchers have discovered a previously unrecognized healing capacity of the heart. In a mouse model, they were able to reverse severe heart failure by silencing the activity of Hippo, a signaling pathway that can prevent the regeneration of heart muscle. During a heart attack, blood stops flowing into the heart; starved for oxygen, part of the heart muscle dies. The heart muscle does not regenerate; instead it replaces dead tissue with scars made of cells called fibroblasts that do not help the heart pump. The heart progressively weakens; most people who had a severe heart attack will develop heart failure.

"One of the interests of my lab is to develop ways to heal heart muscle by studying pathways involved in heart development and regeneration. In this study, we investigated the Hippo pathway, which is known from my lab's previous studies to prevent adult heart muscle cell proliferation and regeneration. When patients are in heart failure there is an increase in the activity of the Hippo pathway. This led us to think that if we could turn Hippo off, then we might be able to induce improvement in heart function."

"We designed a mouse model to mimic the human condition of advanced heart failure. Once we reproduced a severe stage of injury in the mouse heart, we inhibited the Hippo pathway. After six weeks we observed that the injured hearts had recovered their pumping function to the level of the control, healthy hearts." The researchers think the effect of turning Hippo off is two-fold. On one side, it induces heart muscle cells to proliferate and survive in the injured heart, and on the other side, it induces an alteration of the fibrosis. Further studies are going to be needed to elucidate the changes observed in fibrosis.

Mammalian organs vary widely in regenerative capacity. Poorly regenerative organs such as the heart are particularly vulnerable to organ failure. Once established, heart failure commonly results in mortality. The Hippo pathway, a kinase cascade that prevents adult cardiomyocyte proliferation and regeneration, is upregulated in human heart failure. Here we show that deletion of the Hippo pathway component Salvador (Salv) in mouse hearts with established ischaemic heart failure after myocardial infarction induces a reparative genetic program with increased scar border vascularity, reduced fibrosis, and recovery of pumping function compared with controls.

Using translating ribosomal affinity purification, we isolate cardiomyocyte-specific translating messenger RNA. Hippo-deficient cardiomyocytes have increased expression of proliferative genes and stress response genes, such as the mitochondrial quality control gene, Park2. Genetic studies indicate that Park2 is essential for heart repair, suggesting a requirement for mitochondrial quality control in regenerating myocardium. Gene therapy with a virus encoding Salv short hairpin RNA improves heart function when delivered at the time of infarct or after ischaemic heart failure following myocardial infarction was established. Our findings indicate that the failing heart has a previously unrecognized capacity for repair involving more than cardiomyocyte renewal.

Telomere shortening has been identified as one of the primary hallmarks of aging. Mammalian telomeres are structures at the end of linear chromosomes that consist of repeated DNA bound by an array of associated proteins known as shelterin, which prevent chromosome ends from being recognized as double-strand DNA breaks and from chromosome end-to-end fusions. Telomerase is a reverse transcriptase (TERT) that elongates telomeres de novo by adding telomeric repeats on chromosome ends using as template an RNA component (TERC), thus preventing telomere erosion. However, mammalian cells stop expressing telomerase in the majority of tissues after birth, leading to progressive telomere erosion throughout the lifespan of the organism. Telomere shortening has been demonstrated to be sufficient to trigger age-related pathologies and shorten lifespan in mice.

Telomerase reactivation has been envisioned as an strategy to maintain telomeres and therefore to increase the proliferative potential of tissues, both in the telomere syndromes and in age-related conditions. In addition to telomerase, the shelterin complex is also critical for the protection of telomeres. Shelterin consists of six proteins, of which TRF1 is one of the key components. In particular, deletion of TRF1 in mouse embryonic fibroblasts (MEFs) results in induction of senescence, as well as in chromosome fusions and multitelomeric signals (aberrant number of telomeric signals per chromosome end). Importantly, these effects of TRF1 abrogation are independent of telomere length, as TRF1 deletion uncaps telomeres independently of telomerase and cell division. In addition, conditional TRF1 abrogation in various mouse tissues has demonstrated the importance of TRF1 for tissue regeneration and tissue homeostasis. Indeed, high TRF1 levels mark stem cell compartments as well as pluripotent stem cells and are essential to induce and maintain pluripotency.

Given the importance of TRF1 for organismal viability and tissue homeostasis, here we set to address whether TRF1 levels vary with aging in vivo both in mouse and human tissues, as well as to study the potential therapeutic effects of TRF1 increased expression in delaying aging-associated pathologies in vivo. A previous work of our group showed that constitutive TRF1 overexpression acted as a negative regulator of telomere length, mediating telomere cleavage by XPF nuclease. To circumvent this undesired effect of TRF1 overexpression, here we induced moderate and transient TRF1 overexpression in adult (1 year of age) and old (2 years of age) mice using nonintegrative adeno-associated gene therapy vectors (AAV) that can transduce many different tissues but their expression is diluted as cells proliferate.

The results shown here demonstrate that TRF1 levels decrease with age both in mice and in humans. Furthermore, we demonstrate that transient TRF1 expression through the use of AAV9-TRF1 gene therapy in wild-type mice is able to improve mouse physiological health span as indicated by improvements in different markers of aging. AAV9-TRF1 gene therapy significantly prevented age-related decline in neuromuscular function, glucose tolerance, cognitive function, maintenance of subcutaneous fat, and chronic anemia. Interestingly, although AAV9-TRF1 treatment did not significantly affect median telomere length, we found a lower abundance of short telomeres and of telomere-associated DNA damage in some tissues.

The progressive activation and differentiation of satellite cells is critical for proper skeletal muscle growth and muscle regeneration after injury. This cascade is initiated when satellite cells are activated to break quiescence, progress through differentiation, and fuse to nascent or injured muscle fibers. Therefore, elucidating the signals and pathways that regulate this cascade is central to understanding muscle physiology and could provide a foundation for developing novel therapies for the treatment of muscle disorders and regenerative medicine.

Activation of satellite cells occurs in response to a variety of chemical, physical and physiological cues to mediate muscle tissue homeostasis and regeneration. The specialized niche of satellite cells, which are located between the basal lamina and the myofiber, is a critical element in the regulation of satellite cell quiescence and activation. For example, activated Notch signaling, which is directly regulated by proximal extracellular signals, is a well-studied example of a potent pathway that plays an important role in maintaining satellite cell quiescence. In addition, ADAM10, an enzyme known to promote Notch signaling, was found to have a role in the maintenance of the quiescent state. Yet, in spite of the apparent canonical role of Notch signaling in the regulation of satellite cell activation, the extracellular triggers that inhibit Notch signaling and promote satellite cells to break quiescence and differentiate are largely unknown.

Here we describe our discovery that macrophages, which are enriched at the site of muscle injuries, secrete a protein called ADAMTS1 (A Disintegrin-Like And Metalloproteinase With Thrombospondin Type 1 Motif). ADAMTS1 contains two disintegrin loops and three C-terminal thrombospondin type-1 motifs. We established that ADAMTS1 functions as an extracellular signal to satellite cells that promotes activation. We also found that constitutive overexpression of Adamts1 in macrophages accelerates satellite cell activation and muscle regeneration in young mice. Our data indicate that the mechanism of this ADAMTS1 activity is by targeting NOTCH1 protein on the satellite cells. These findings significantly enrich our understanding of the extracellular signals that regulate satellite cell activation and identify a pathway that could potentially be targeted with therapeutics to enhance muscle regeneration.

Even in end-stage retinal degeneration such as retinitis pigmentosa (RP), the remaining retinal layers and central visual projections remain structurally intact. Stimulation of these remaining cells is potentially sufficient to mimic visual responses and restore vision, and by this means the subretinal electronic implant has shown proof of principle for restoration of vision in patients after severe photoreceptor loss. An alternative gene therapy strategy involves the expression of transgenes encoding photosensitive proteins in remaining retinal cells, making them directly light sensitive in the absence of rods and cones.

A candidate protein for this purpose is melanopsin, the photopigment naturally present in a subset of ganglion cells that are intrinsically photosensitive - intrinsically photosensitive retinal ganglion cells (ipRGCs). Melanopsin is particularly suited to this purpose since it is native to the human eye and therefore is less likely to be immunogenic. Melanopsin shows greater sensitivity to light than alternative microbial optogenetic tools, such as channelrhodopsin-2 or halorhodopsin.

Previous work used intravitreal delivery of an adeno-associated viral (AAV) vector to express mouse melanopsin in ganglion cells with restoration of visual responses. We investigated whether human melanopsin could be effectively delivered via an alternative subretinal approach, using a ubiquitous (CBA) promoter to drive expression in all remaining outer retinal cells for several reasons. Subretinal vector delivery is well established in human clinical trials but has not been assessed in combination with a CBA promoter as an optogenetic approach for vision restoration. Transduction of cells in the upstream retina maximizes the potential of retaining complex processing of the visual signal. Furthermore, increased availability of chromophore in the outer retina may be required for effective photon capture in the absence of specialized outer segment discs. Other studies have used AAV vectors containing an enhancer to target a melanopsin-mGluR6 chimera or rhodopsin via intravitreal injection. However, there is variation in anatomy between primates and mouse models, and this may render the intravitreal approach less effective in humans. The increased risks of an inflammatory response following intravitreal AAV injection may also limit the translational potential of this route of delivery.

We therefore assessed transduction after subretinal delivery of melanopsin and whether this could support long-term restoration of light sensitivity and visual function in a mouse model of end-stage RP. Ectopically expressed melanopsin mediated depolarization of outer retinal cells and ultimately ganglion cell action potential firing, resulting in long-term restoration of the pupil light reflex and behavioral light avoidance up to at least 13 mo following injection. Finally, subretinal melanopsin expression led to light-induced changes in visual cortex blood flow and provided long-term improvements in a visually guided behavioral task that requires image-forming vision. In combination, these results suggest that this approach may be clinically useful in vision restoration in patients with end-stage RP.

As in other poikilotherms, longevity in C. elegans varies inversely with temperature; worms are longer-lived at lower temperatures. While this observation may seem intuitive based on thermodynamics, the molecular and genetic basis for this phenomenon is not well understood. In C. elegans, animals that develop and age at 15 °C ('low temperature') are long-lived compared to wild-type animals grown at 20 °C (room temperature), whereas wild-type worms that develop and age at 25 °C ('high temperature') are short-lived compared to wild-type worms grown at 15 °C or 20 °C. This 'temperature law' has been described as widely accepted, but not tested beyond limited number of strains.

While the 'temperature law' is observed among wild-type organisms, the interplay between genetics and temperature is not well understood. Multiple recent reports suggest that the effects of temperature on longevity are genetically controlled and that both heat and cold modify transcriptional pathways that effect lifespan. To better understand the interplay between temperature and longevity, we measured the lifespans of worms with genetic manipulations known to affect longevity at 15 °C, 20 °C, or 25 °C. We found six examples of how longevity can be impacted across temperatures, representing conditions that: robustly increase lifespan at all temperatures (daf-2 RNAi); robustly decrease lifespan at all temperatures (rhy-1(ok1402)); decrease lifespan at high but not low temperature (daf-16(mu86)); increase lifespan at high temperature but decrease lifespan at low temperature (rsks-1(ok1255)); increase lifespan at low temperature but not high temperature (cep-1(gk138)); and do not alter lifespan at any temperature (cah-4 RNAi).

Having established that relative longevity can vary across temperatures, we next asked whether this variability is common among conditions known to modify longevity. We tested nearly fifty genotypes and interventions previously reported to affect lifespan and found that relative longevity was consistently inconsistent across temperatures. However, there are consistent trends within longevity pathways, where strains/conditions known to have opposing effects are also affected by temperature oppositely. In summary, we find significant interaction between longevity interventions and environmental temperature in two-thirds of the cases examined, indicating that a temperature-independent effect on longevity is more the exception than the rule. This variation confirms that genetics play a substantive role in temperature-dependent longevity that cannot be explained solely by the rules of thermodynamics and chemical kinetics. The observed variation in relative longevity with temperature is consistent with the hypothesis that a distinct set of mechanisms determine nematode longevity at different temperatures.

It has been suggested that protein quality control and the heat stress response are of primary importance for determining nematode longevity at 25 °C. Our data support this model; we find interventions that limit heat stress response (e.g., daf-16(mu86)) are detrimental at high, but not low, temperature, while interventions that improve protein homeostasis, such as dietary restriction or reduced expression of translation machinery (e.g., rsks-1(ok1255), rpl-6 RNAi), show lifespan extension at high temperature. The relevant mechanisms affecting longevity at low temperature are less clear, particularly because relatively few aging studies are conducted at 15 °C compared to 20 °C or 25 °C. Our results demonstrate that the impact of temperature on relative lifespan is of greater importance than generally appreciated by the C. elegans aging field. The vast majority of published studies report the impact of different interventions on lifespan at a single temperature, usually either 20 °C or 25 °C. We suggest that studies reporting effects on lifespan should typically be performed at more than one temperature to understand the robustness of the effect and the interaction with temperature.

A recent paper describes a new approach to bone regeneration; stimulating cells to produce vesicles which can then be delivered to facilitate tissue regeneration. The researchers believe that the findings mark the first step in a new direction for tissue regeneration with the potential to help repair bone, teeth and cartilage. Current approaches have significant limitations; autologous grafts cannot meet demand and cause patient morbidity, allogeneic bone lacks bioactive factors, and growth factor-based approaches (e.g. BMP-2) may have serious side-effects and high costs. Consequently, there is a considerable need to devise new methods for the generation of large volumes of bone without associated patient morbidity.

In recent years, attention has been focused on cell-based approaches. However, translation is frequently prevented by insurmountable regulatory, ethical and economic issues. This novel solution delivers all the advantages of cell-based therapies but without using viable cells, by harnessing the regenerative capacity of nano-sized particles called extracellular vesicles that are naturally generated during bone formation. Excitingly, the team have shown in-vitro that if extracellular vesicles are applied in combination with a simple phosphate the therapy outperforms the current gold standard, BMP-2. "It is early days, but the potential is there for this to transform the way we approach tissue repair. We're now looking to produce these therapeutically valuable particles at scale and also examine their capacity to regenerate other tissues."

Is the rise in life expectancy in the West coming to an end? This year the Office for National Statistics (ONS) announced something depressing: a slight fall in life expectancy for pensioners - six months for women and four for men. Overall, life expectancy is still rising but at a much slower rate than everyone thought it would. There is no shortage of experts out there prepared to explain why life expectancy has stalled. Maybe it's a result of the financial crisis, a failure of elderly care linked to austerity? Maybe it's obesity, something that could even make today's young the first generation to live shorter lives than their parents? Or maybe it is just that we are already close to the outer limits of possibility when it comes to life expectancy?

Yet look a little closer and talk to longevity experts and healthcare investors and a different picture emerges. The slowdown in life expectancy actually comes at a time when the science of ageing is getting very exciting. Much of the rise in life expectancy of the past 50 years has been down to environmental effects: the near eradication of real poverty in the West; the rise of universal medical treatment; antibiotics; better air quality; improved working conditions. All these things should keep adding a little more to the numbers. They are also just the beginning. Next will come an enhanced understanding of what actually causes ageing and how it can be stalled, alongside the start of mass molecular fiddling.

The new book Juvenesence: Investing in the Age of Longevity forecasts that within the next 20 years average life expectancy in the developed world will rise to between 110 and 120. This makes the authors happy. Their book is full of soothing thoughts. That's going to sound lovely to most people. But you can bet there is a large group who find it totally terrifying: policymakers. Ageing populations are very expensive. Our systems aren't yet in any way equipped to cope with the odd half a million 90-year-olds the UK has already, let alone millions of 100-year olds. Our health and welfare systems were designed for a different era, and the unfunded liabilities of public and private pension funds are the kind of thing that never get addressed.

This should make individuals worry, too. Very few people have planned properly for their own retirements - and even if they have, extended longevity will mean that the assumptions on which they have based their calculations are entirely wrong. On top of this, almost no one will have planned for the fact that this will make governments that don't seriously reform - my guess is that's all of them - increasingly broke. Nor will they have planned for the obvious next step: that cash-strapped governments look to other people's capital for help. If we do enter a new age of the long-lived, it will probably be less an age of the happy rentier than the very heavily taxed rentier. If you don't want to spend your 11th decade wishing that longevity science had never become a thing, think of what you once thought you should save for your retirement and triple it. Golden years? Working years.

So from around age 20 (or younger) the thymus begins to shrink and loses the ability to produce T cells, why does this happen?

Nobody knows why thymic atrophy, or involution, occurs, but it happens in all vertebrates, starting really at the age of puberty. Some have suggested that it happens to save energy, since the production of properly qualified T cells is very energy intensive and inefficient, and of course, at puberty, the body begins to devote more energy to reproduction, which might require a tradeoff against using energy for immune maintenance. This could be adaptive since, in nature, humans would not have lived long enough for immune system collapse to set in, even though today, the situation is different. Regardless of the evolutionary reason for it, the most immediate biochemical cause of involution seems to be mostly a drop in thymic FOXN1 expression, although some have pointed to a decline in intra-thymic IL-7 and the negative influence of circulating sex hormones, for example.

You recently ran a human clinical trial to regrow the thymus gland. Can you please tell us what is the main goal of the project and what is the progress?

The trial was conducted under an FDA-approved IND and with review from multiple scientific and ethics committees. It consisted of a 12-month treatment course for 9 men divided into two cohorts, with the first cohort starting in October of 2015 and the second ending in April of this year. Our goal was to gather preliminary evidence indicating that it is possible to safely regenerate the normal aging human thymus and restore its functions, essentially reversing the process of age-related immunological deterioration. We chose to work with healthy men in part because this was a small trial, which required a reasonably uniform population, and in part because more information was available for men than for women. We chose an age range of 50 to 65 years because this range extends from several years before to a few years after the threshold age at which the immune system tends to collapse. Success would therefore suggest the possibility of preventing or even reversing the early stages of immune collapse. In future trials, we intend to enroll both women and older men.

The outcome measures included MRI evaluation of thymic density before and after treatment, simple and sophisticated assessment of T cell population distributions, measurements of many serum factors related to immune system function and general health, lymphocyte telomere length distributions and telomerase activity, and biological age based on the Horvath epigenetic clock. Regarding our results, first of all, when you're working with human beings, safety has to be the top priority, so I'm glad to be able to say that we met or exceeded all of our safety targets. Regarding thymic imaging results, preliminary analyses indicate that there was a consistent and substantial increase in thymic density, which indicates replacement of thymic fat with more water-rich material, and in previous studies on human immunodeficiency patients, this coincided with improved thymic function. Superficial tests of immune system aging showed improvements in 8 out of 9 men, and we were able to identify a possible correctable reason for the failure of the 9th volunteer. Men of all ages were able to respond positively and to avoid side effects. However, the most definitive endpoints of our study are still being analyzed at four different locations around the world, so we won't really know the final results of our study for probably another month or two.

Are we going to see a publication anytime soon?

I'm not sure about soon, but certainly, as soon as we can. This will be a complicated paper with lots of authors and lots of data to present, but also with top-tier academic co-authors who can help us go through the scientific review process quickly. In any case, we certainly want to make sure that any novel results are shared with the broader medical and scientific communities.

We are Nina Torres Zanvettor and Nicolas Chernavsky, professional translators from Campinas (Brazil). Nicolas graduated as a journalist in USP (University of São Paulo) and has 13 years of experience as a translator. Nina graduated in Chemistry in Unicamp (University of Campinas), has a master degree in Inorganic Chemistry by Unicamp as well and works as a translator and a English teacher. The translation project of Ending Aging into Portuguese was created after Aubrey de Grey came to Brazil for the first time, in February of 2017. In that occasion, we met Aubrey after his talk at Campus Party, in São Paulo. We talked about the possibility of helping SENS using our professional experience in English-Portuguese translation. The scientific specialization of Nina together with the linguistic knowledge of Nicolas, mixed with a great dose of passion for the end of aging, could result in a translated version that would bring the ideas of the book to Portuguese speakers.

When we get sick and need medical assistance, or take a medicine or even go through a surgery, we realize the importance of healthcare. However, nowadays, medical science has still a lot of limitations. Diseases like Parkinson's, Alzheimer's, cancer and cardiovascular diseases are still practically inescapable when we reach a certain age. That's why the modern medicine is realizing that in order to defeat these diseases, we will have to face something that is difficult to face: aging. Only by defeating aging we could defeat these diseases, because they are the final phase of aging itself, which, in physical terms, is the accumulation of damage throughout our life at the cellular and molecular level.

Thus, this new area of medicine, focused on the aging issue, can give more decades of life to everyone. One of the world's most important scientists in this area, the British biogerontologist Aubrey de Grey, proposes a pathway so that in a few decades, probably still during the lifetime of most of the people still alive, we could build therapies to repair the damage caused by aging. The pathway proposed by Aubrey de Grey is called SENS (Strategies for Engineered Negligible Senescence). He identified seven basic types of cellular and molecular damage which result on aging: the mutations of our chromosomes, the glycation, the formation of extracellular and intracellular aggregates, the cellular senescence, the reduction of stem cell reserves and mitochondrial mutations. For each one of these forms of damage, Aubrey de Grey proposes a repair therapy.

Supporting this project, you are helping to spread knowledge in the area and to accelerate scientific research, contributing to the end of aging. We need the help of everybody in this journey towards the end of aging, and in this context, it's important to notice that the Portuguese language is the sixth most spoken language in the world, spoke by 273 million of people. Besides, in order for these technologies to reach everybody, this knowledge needs to reach everybody as well, including the Portuguese speaking world.

The premise that larger body size leads to reduction in lifespan longevity has generally been substantiated through scientific research over the past 40 years. For example, research suggests smaller body size is generally better for one's health, and is supported by robust cross-cultural findings of average lifespan reduction with increasing height observed in groups such as deceased American male veterans, French males and females who died before the year 1861 and males born in Sardinia, Italy between 1866 and 1915. While the biological reason for the relationship between height and lifespan longevity in humans is not yet fully understood, it is difficult to ignore the potential profound effect of genetics on lifespan longevity. A study on 8,006 American men of Japanese ancestry found height was positively associated with mortality, and perhaps of more interest, was the first to conclusively link the "longevity gene" FOX03 to smaller body size and greater lifespan longevity in humans.

Although a sizeable amount of evidence suggests that larger body size independently reduces longevity, it also important to recognize confounders of this relationship that affect biological parameters independent of body size characteristics, such as differences in genotypes, socioeconomic status (SES), education, medical care, relative weight, hygienic practices, nutrition, and lifestyle choices such as engaging in regular exercise and avoiding smoking. Further, it has been suggested that height generally explains less than 10% of the proportion of variance regarding longevity, and researchers surmise that the lack of consensus on the degree to which height affects longevity is likely due to the impact of these extraneous variables.

If height indeed influences longevity independently, deceased professional basketball players represent a promising group to further investigate this phenomenon in given their general exceptional height and relative homogeneity of other confounders such as affluence (particularly in the more recent decades), where the higher SES/social status may result in less confounding by factors such as ethnicity. We hypothesized that when adjusting for birth decade, exceptionally taller players will have died at relatively younger ages. The population of this study was comprised of living and deceased players who played in the National Basketball Association (NBA), debut between 1946-2010, and/or the American Basketball Association (ABA), debut between 1967-1976.

Overall, 3,901 living and deceased players were identified and had a mean height of 197.78 cm, and of those, 787 former players were identified as deceased with a mean height of 193.88 cm. Descriptive findings indicated that the tallest players (top 5%) died younger than the shortest players (bottom 5%) in all but one birth decade (1941-1950). Similarly, survival analyses showed a significant relationship between height and lifespan longevity, where taller players had a significantly higher mortality risk compared to shorter players (hazard ratio: 1.30). As many players have superior height compared to the age- and sex-matched average height of the US general population, there appears to be a curvilinear relationship between height and longevity where the magnitude of mortality risk decreases past a certain threshold. However, smaller sample sizes in the younger players may have been driving this effect. From a general population perspective, it is unclear whether there is a threshold for the apparent longevity benefits from having smaller body size.

Being overweight or obese are associated with increased risk of 13 types of cancer. These cancers account for about 40 percent of all cancers diagnosed in the United States in 2014, according to the latest Vital Signs report by the Centers for Disease Control and Prevention (CDC). The Vital Signs report analyzed 2014 cancer incidence data from the United States Cancer Statistics report and reviewed data from 2005 to 2014 to determine trends. About 630,000 people in the U.S. were diagnosed with a cancer associated with being overweight or obese in 2014. About 2 in 3 occurred in adults 50- to 74-years-old. Cancers associated with being overweight or obese, excluding colorectal cancer, increased 7 percent between 2005-2014. Colorectal cancer decreased 23 percent, due in large part to screening. Cancers not associated with being overweight or obese decreased 13 percent.

In 2013-2014, about 2 out of 3 adults in the U.S. were overweight (defined as having a body mass index of 25-29.9 kg/m2) or had obesity (having a body mass index of 30 kg/m2 and higher). The body mass index (BMI) is a person's weight (in kilograms) divided by the square of the person's height (in meters). Many people are not aware that being overweight and having obesity are associated with some cancers. The International Agency for Research on Cancer (IARC) has identified 13 cancers associated with being overweight or obese: meningioma, multiple myeloma, adenocarcinoma of the esophagus, and cancers of the thyroid, postmenopausal breast, gallbladder, stomach, liver, pancreas, kidney, ovaries, uterus, colon and rectum (colorectal).