Idiopathic pulmonary fibrosis is a potentially lethal disease associated with the presence of critically short telomeres, currently lacking effective treatment. Researchers have succeeded in curing this disease in mice using a gene therapy that lengthens the telomeres. Telomeres are protein structures located at the ends of each chromosome; like caps, they protect the integrity of the chromosome when the cell divides. But telomeres only fulfill their protective function if they are long enough; when they shorten too much, the damaged cells cease to divide preventing tissue regeneration. Short telomeres are associated with ageing - as age increases, cells accumulate more divisions and more telomeric shortening - and also with several diseases. Pulmonary fibrosis is one of them.

In lung fibrosis, the lung tissue develops scars that cause a progressive loss of respiratory capacity. Environmental toxins play an important role in its origin, but it is known that there must also be telomeric damage for the disease to appear. Patients with pulmonary fibrosis have short telomeres whether the disease is hereditary - it runs into the family - or not. The most likely explanation is that when the telomeres become too short, the damaged cell activates a 'repair program' that induces scar formation that leads to fibrosis.

Researchers decided to address the problem about five years ago, starting with the development of an animal model that faithfully reproduces the human disease. The most widely used model until then was to apply bleomycin into the mouse lungs to induce damage, in an attempt to reproduce the environmental insult. However, in these animals the disease goes into remission in a few weeks and there is not telomere shortening. The researchers sought after a mouse model in which the environmental damage synergized to that produced by short telomeres, that is what happens in human pulmonary fibrosis. They succeeded in 2015.

The treatment consisted of introducing the telomerase gene into the lung cells using gene therapy. The researchers first modified a virus innocuous to humans (known as vectors) so that their genetic material incorporated the telomerase gene, and then injected those vectors into the animals. The basis of this work is the hypothesis that age-associated diseases can be treated by targeting the molecular and cellular processes of ageing, specifically telomere shortening. In 2012, the researchers generated mice that not only lived longer but also showed improved health by treating them with telomerase. Their work since then has aimed to develop this therapy to specifically treat age-associated diseases and telomere syndromes.

Pulmonary fibrosis is a fatal lung disease characterized by fibrotic foci and inflammatory infiltrates. Short telomeres can impair tissue regeneration and are found both in hereditary and sporadic cases. We show here that telomerase expression using AAV9 vectors shows therapeutic effects in a mouse model of pulmonary fibrosis owing to a low-dose bleomycin insult and short telomeres. AAV9 preferentially targets regenerative alveolar type II cells (ATII).

AAV9-Tert-treated mice show improved lung function and lower inflammation and fibrosis at 1-3 weeks after viral treatment, and improvement or disappearance of the fibrosis at 8 weeks after treatment. AAV9-Tert treatment leads to longer telomeres and increased proliferation of ATII cells, as well as lower DNA damage, apoptosis, and senescence. Transcriptome analysis of ATII cells confirms downregulation of fibrosis and inflammation pathways. We provide a proof-of-principle that telomerase activation may represent an effective treatment for pulmonary fibrosis provoked or associated with short telomeres.

Atherosclerosis is the most significant human health problem globally. We know today that the disease does not follow a simple, unidirectional progression, and is determined by a myriad of pathways, control mechanisms, and repair processes; these encompass multiple inflammatory molecules, bone marrow (BM)-derived progenitor cells, a range of immune cells such as specific monocyte subpopulations, genetic mutations, and epigenetic modifications among numerous other participants both known and those yet to be discovered. Ultimately, however, the clinical result for an immensely large number of individuals is the formation and growth of vascular lesions with the potential to rupture, leading to life-threatening conditions. It is imperative to continue to evolve technological strategies to both predict and detect the formation, progression, and clinical status of these atherosclerotic plaques, while additional details are elucidated regarding the process of disease progression.

One example of important progress has been made in the control of inflammation when inflammation is no longer promoting repair, but instead has taken a damaging role for the artery. It was recently reported that a monoclonal antibody against IL1-beta, when injected systemically to patient with cardiovascular disease and high inflammatory index, is capable of reducing risk for coronary events, even with already reduced lipids and had no further effect on lipid levels. The role of inflammation is increasingly established in the progression of arterial lesions, and it is useful to consider inflammation in the context of arterial homeostasis.

Arterial repair is triggered and controlled by molecules that belong to inflammatory pathways. However, as was hypothesized and subsequently demonstrated in an animal model, the progression of atherosclerotic inflammation is modulated by the presence or the absence of an efficient repair process. In the presence of BM vascular progenitor cells capable of arterial repair, the artery heals and inflammatory signals subside and vanish. However, reductions in the availability of BM-derived vascular progenitor cells occurring as a consequence of aging or genetic susceptibility (exhaustion or dysfunction) result in a lack of arterial healing.

These reductions can occur either because repair-capable cells are no longer produced effectively by the BM, because the produced cells have become dysfunctional, or a combination thereof. Consequently, inflammatory signals do not subside and vanish, and indeed are heightened to the point where they attract and support monocytes/macrophages and other immune competent cells that further enhance arterial injury. Hence, the maintenance of arterial homeostasis is a complex process that must balance injuries to the arterial wall, inflammatory processes required for triggering and supporting arterial repair, and the renewal of BM-derived vascular progenitor cells that are necessary for such repair.

Arterial stiffness is a characteristic feature of normal arterial aging, but is also associated with accelerated cardiovascular disorders. Another age-related process is arterial calcification, which in turn is a known risk predictor that increases morbidity and mortality in cardiovascular diseases. MicroRNAs (miRNAs) are small non-coding RNAs that downregulate their target gene expression post-transcriptionally. They are widely studied in recent years and their role in cardiovascular dysfunction is to some extent revealed. Identification of over- or underproduction of miRNAs could be therapeutic targets for prevention and treatment of vascular diseases.

Arterial stiffness results from complicated interactions between multiple components of the vessel wall, including extracellular matrix (ECM) composition, vascular smooth muscle cell (VSMC), and endothelial dysfunction. Collagen and elastin are the most important structural proteins of ECM and key regulators of arterial stiffness as they are responsible for blood vessels' strength and elasticity. Reconstruction of ECM, notably increased levels of aberrant types of collagen and reduction of elastin, appears to be the most important mechanism contributing to arterial stiffness. Matrix metalloproteases (MMPs) are endopeptidases which degrade all kinds of ECM proteins. Thus they play a significant role in arterial stiffness via regulating collagen and elastin levels in ECM.

Moreover, advanced glycation end products (AGEs) contribute to arterial stiffness through cross-linking with ECM proteins, including collagen, which reduces vessel's flexibility. Furthermore, many hormones and cytokines are involved in aortic stiffness, such as angiotensin II (Ang II) which promotes arterial stiffness through regulating signaling pathways that result in altered ECM accumulation and increased vascular tone. Apart from structural abnormalities, VSMC proliferation, migration and calcification, as well as impaired endothelium-dependent dilation through paracrine molecules such as nitric oxide (NO) and endothelin are, also, implicated in the development of arterial stiffness.

Extensive research during the last decade confirmed the association of miRNAs with cardiovascular diseases. MiRNAs seem to play a significant role in arterial stiffness and calcification through modulating critical pathways and molecules such as TGF-β and BMP signaling, Ang II, MMP activity, Runx, and phenotypic switch of VSMC. Thus, they may be used as therapeutic targets or diagnostic markers in the future to decrease arterial stiffness and prevent the development of cardiovascular diseases. However, it is more than obvious that the molecular biology and pathophysiology is very complex. Many miRNAs might have the same target gene (e.g., Runx2 is suppressed by miR-30b-c but enhanced by miR-32), while a single miRNA might exert multiple functions by targeting more than one genes and affecting different pathways with opposing results (e.g., miR-29, miR-19b and their role in fibrosis). Futhermore, miR-145, one of the most important miRNAs in cardiovascular pathophysiology, decreases arterial stiffness by inhibiting TGF-β signaling while, on the contrary, TGF-β activates miR-145 to promote the contractile phenotype of VSMCs and reduce arterial stiffness as well. Targeting TGF-b through miR-145 might have controversial results. To conclude, additional clinical and laboratory research should be continued for the establishment of miRNAs as treatment targets and biomarkers of cardiovascular diseases.

Your foundation is working on an initiative requiring 50 million in funding-

Well, if we had 50 million per year in funding, we could go about three times faster than we are on 5 million per year.

And you're looking at a 2021 timeframe to start human trials?

That's approximate. Remember, because we accumulate in the body so many different types of damage, that means we have many different types of therapy to repair that damage. And of course, each of those types has to be developed independently. It's very much a divide and conquer therapy. The therapies interact with each other to some extent; the repair of one type of damage may slow down the creation of another type of damage, but still that's how it's going to be. And some of these therapies are much easier to implement than others. The easier components of what we need to do are already in clinical trials - stem cell therapies especially, and immunotherapy against amyloid in the brain, for example. Even in phase III clinical trials in some cases. So when I talk about a timeframe like 2021, or early 20s shall we say, I'm really talking about the most difficult components.

What recent strides are you most excited about?

Looking back over the past couple of years, I'm particularly proud of the successes we've had in the very most difficult areas. If you go through the seven components of SENS, there are two that have absolutely been stuck in a rut and have gotten nowhere for 15 to 20 years, and we basically fixed that in both cases. We published two years ago in Science magazine that essentially showed a way forward against the stiffening of the extracellular matrix, which is responsible for things like wrinkles and hypertension. And then a year ago, we published a real breakthrough paper with regard to placing copies of the mitochondria DNA in the nuclear DNA modified in such a way that they still work, which is an idea that had been around for 30 years; everyone had given up on it, some a long time ago, and we basically revived it.

What do you think are the biggest barriers to defeating aging today: the technological challenges, the regulatory framework, the cost, or the cultural attitude of the "pro-aging" trance?

One can't really address those independently of each other. The technological side is one thing; it's hard, but we know where we're going, we've got a plan. The other ones are very intertwined with each other. A lot of people are inclined to say, the regulatory hurdle will be completely insurmountable, plus people don't recognize aging as a disease, so it's going to be a complete nonstarter. I think that's nonsense. And the reason is because the cultural attitudes toward all of this are going to be completely turned upside down before we have to worry about the regulatory hurdles. In other words, they're going to be turned upside down by sufficiently promising results in the lab, in mice. Once we get to be able to rejuvenate actually old mice really well so they live substantially longer than they otherwise would have done, in a healthy state, everyone's going to know about it and everyone's going to demand - it's not going to be possible to get re-elected unless you have a manifesto commitment to turn the FDA completely upside down and make sure this happens without any kind of regulatory obstacle.

I've been struggling away all these years trying to bring little bits of money in the door, and the reason I have is because of the skepticism as to regards whether this could actually work, combined with the pro-aging trance, which is a product of the skepticism - people not wanting to get their hopes up, so finding excuses about aging being a blessing in disguise, so they don't have to think about it. All of that will literally disintegrate pretty much overnight when we have the right kind of sufficiently impressive progress in the lab. Therefore, the availability of money will also open up. It's already cracking: we're already seeing the beginnings of the actual rejuvenation biotechnology industry that I've been talking about with a twinkle in my eye for some years.

I'm sure you hate getting the timeline question, but if we're five years away from this breakthrough in mice, it's hard to resist asking - how far is that in terms of a human cure?

When I give any kind of timeframes, the only real care I have to take is to emphasize the variance. In this case I think we have got a 50-50 chance of getting to that tipping point in mice within five years from now, certainly it could be 10 or 15 years if we get unlucky. Similarly, for humans, a 50-50 chance would be twenty years at this point, and there's a 10 percent chance that we won't get there for a hundred years.

You famously said ten years ago that you think the first person to live to 1000 is already alive. Do you think that's still the case?

Definitely, yeah. I can't see how it could not be. Again, it's a probabilistic thing. I said there's at least a 10 percent chance that we won't get to what I call Longevity Escape Velocity for 100 years and if that's true, then the statement about 1000 years being alive already is not going to be the case. But for sure, I believe that the beneficiaries of what we may as well call SENS 1.0, the point where we get to Longevity Escape Velocity, those people are exceptionally unlikely ever to suffer from any kind of ill health correlated with their age. Because we will never fall below Longevity Escape Velocity once we attain it.

Could someone who was just born today expect-

I would say people in middle age now have a fair chance. Remember - a 50/50 chance of getting to Longevity Escape Velocity within 20 years, and when you get there, you don't just stay at biologically 70 or 80, you are rejuvenated back to biologically 30 or 40 and you stay there, so your risk of death each year is not related to how long ago you were born, it's the same as a young adult. Today, that's less than 1 in 1000 per year, and that number is going to go down as we get self-driving cars and all that, so actually 1000 is a very conservative number.

For scientists, policy makers, regulators, government officials, investors and other stakeholders, a consensus understanding of the field of human longevity remains fragmented, and has yet to be systematized by any coherent framework, and has not yet been the subject of a comprehensive report profiling the field and industry as a whole by any analytical agency to date. Experts on the subject of human longevity, who tend arrive at the subject from disparate fields, have failed even to agree on a likely order of magnitude for future human lifespan. Those who foresee a 100-year average in the near future are considered extreme optimists by some, while others have even mooted the possibility of indefinite life extension through comprehensive repair and maintenance. As such the longevity industry has often defied real understanding and has proved a complex and abstract topic in the minds of many, investors and governments in particular.

A report entitled 'The Science of Longevity', standing at almost 800 pages in length, seeks to rectify this. Part 1 of the report ties together the progress threads of the constituent industries into a coherent narrative, mapping the intersection of biomedical gerontology, regenerative medicine, precision medicine, and artificial intelligence, offering a brief history and snapshot of each. Part 2 lists and individually profiles 650 longevity-focused entities, including research hubs, non-profit organizations, leading scientists, conferences, databases, books and journals. Infographics are used to illustrate where research institutions stand in relation to each other with regard to their disruptive potential: companies and institutions specialising in palliative technologies are placed at the periphery of circular diagrams, whereas those involved with more comprehensive, preventative interventions, such as rejuvenation biotechnologies and gene therapies, are depicted as central.

Since these reports are being spearheaded by the UK's oldest biomedical charity focused on healthspan extension, the Biogerontology Research Foundation is publishing them online, freely available to the public. While the main focus of this series of reports is an analytical report on the emerging longevity industry, the reports still delve deeply into the science of longevity, and Volume I is dedicated exclusively to an overview of the history, present and future state of ageing research from a scientific perspective. Volume 2, is set to be published shortly thereafter, and will focus on the companies and investors working in the field of precision preventive medicine with a focus on healthy longevity, which will be necessary in growing the industry fast enough to avert the impending crisis of global aging demographics.

These reports will be followed up throughout the coming year with Volume 3 ("Special Case Studies"), featuring 10 special case studies on specific longevity industry sectors, such as cell therapies, gene therapies, AI for biomarkers of aging, and more, Volume 4 ("Novel Longevity Financial System"), profiling how various corporations, pension funds, investment funds and governments will cooperate within the next decade to avoid the crisis of demographic aging, and Volume 5 ("Region Case Studies"), profiling the longevity industry in specific geographic regions.

The greatest problem threatening global economic prosperity and social stability is demographic aging. The only sustainable solution is to extend healthy lifespan (healthspan). Clearly it would be desirable to add life to our years rather than merely years to our lives. But few are aware that health span extension is becoming routine in the laboratory. Scientific breakthroughs have demonstrated up to 30% increased healthspan extension in mice, and much more in non-mammalian model organisms by various pharmacological, environmental, and genetic interventions. In recent years, scientists have elucidated the fundamental mechanisms or hallmarks of aging, opening the field of geroscience - the understanding and manipulation of the fundamental biological processes in age-related disease.

The widest ceiling over the aspirations of geroscience has always been the inextricability of disease from aging and the inextricability of aging from human metabolism, which, being so complex and integral to our day-to-day functioning, can only be amended rather than reconstructed. This limits us because it robs us of the most obvious approach to radical life extension: radical interference in human metabolism. For just as we might like to be able to alter a car's inner workings so that they inflict less wear and tear, so too might we like to be able to somehow rearrange metabolism so that it inflicts less wear and tear on body tissues.

Sadly this is not an option. While subtle interventions in areas such as calorie restriction mimetics hold some promise to appreciably increase life expectancy, anything amounting to a successful radical intervention in metabolism which radically extends life span is inconceivable for the foreseeable future for the above reasons. This brings us to the alternative approach to vehicle longevity: repair and maintenance. Which in human terms means the continuous restoration of human tissues, irrespective of the various processes that age them.

These two approaches differ starkly. The former could be thought of as like meddling with the inner mechanisms of a clock, cogs and all, in order to slow it down. The latter could be imagined as forcing back the hands of a clock, setting back the progress, while inner clockwork, the process, remains unaffected. In human terms 'setting back the hands' means taking knowledge obtained by geroscience, fashioning it into a damage report and devising a repair strategy. And just as setting back a clock does not require the same extensive knowledge of horology as would be involved with meddling with the clockwork, nor does the restoration of aging tissue require an unfeasibly extensive knowledge of geroscience, only enough to enumerate the manifest differences between old and young tissue. So could we then aspire to repair these enumerated damages comprehensively enough and rapidly enough to appreciably postpone disease? In other words might there be an extent to which we can afford to allow aging to proceed as it normally does while simultaneously clearing up the damage it leaves behind, kicking the can disease down the road?

We are in effect describing the application of regenerative medicine to aging. Regenerative medicine is an area of biotechnology which aims to restore damaged tissues and organs. So why not tissues and organs damaged by the miscellaneous ravages of age?

Epidemiological, experimental, and clinical studies have suggested that age-related cerebrovascular dysfunction plays a critical role in the pathogenesis of dementia, including Alzheimer's disease (AD). Amyloid β (Aβ), the main constituent of amyloid plaques and a key pathogenic factor in AD, has detrimental effects on cerebral blood vessels resulting in disruption of homeostatic function of the cerebrovascular endothelial cells. The present study was designed to determine the effects of senescence and angiotensin II (Ang II) on expression and processing of amyloid precursor protein (APP) in human brain microvascular endothelial cells (BMECs).

Cellular senescence is an important contributor to aging and age-related diseases. Prior studies provided evidence that processing of endogenous APP is down-regulated in senescent human fibroblasts, but the effects of senescence on APP expression and processing in vascular endothelium have not been studied. APP is highly expressed in endothelium and can be processed by two major proteolytic pathways. In the non-amyloidogenic pathway, APP is cleaved by α-secretase thereby generating soluble APPα (sAPPα), a well-known anticoagulant, neurotrophic, and neuroprotective molecule. In contrast, amyloidogenic processing of APP sequentially driven by β-site APP cleaving enzyme (BACE1) and γ-secretase generates cytotoxic Aβ. Under pathological conditions, β-processing of APP is activated therefore increasing production of Aβ. Importantly, inhibition of BACE1 could prevent or reduce the accumulation of Aβ in the brain, thereby reducing AD-related pathology. Not surprisingly, inhibitors of BACE1 are currently being developed for the treatment of AD.

Taken together, the results of the present study suggest that reduced APP expression contributes to down-regulation of sAPPα in senescent brain microvascular endothelium. Increased BACE1 expression and Aβ production suggest that senescence promotes β-processing of APP. Treatment with a BACE1 inhibitor is beneficial for senescent human BMECs. This effect is mediated by shifting of APP processing towards non-amyloidogenic pathway. The present study also reports a novel observation regarding the detrimental effects of Ang II on α-processing of APP by activation of AT2R in senescent human BMECs. Given the fact that the cleavage products of APP play an important role in vascular homeostasis, we propose that increased Aβ production together with loss of sAPPα are previously unrecognized mechanisms of cerebral microvascular endothelial dysfunction induced by senescence and Ang II. Our findings support the concept that pathological expression and processing of APP in senescent cerebrovascular endothelium may play an important role in pathogenesis of cerebral amyloid angiopathy and AD.

The relationship between human cytomegalovirus (HCMV) infections and accelerated immune senescence is controversial. Whereas some studies reported a CMV-associated impaired capacity to control heterologous infections at old age, other studies could not confirm this. We hypothesized that these discrepancies might relate to the variability in the infectious dose of CMV occurring in real life. Here, we investigated the influence of persistent CMV infection on immune perturbations and specifically addressed the role of the infectious dose on the contribution of CMV to accelerated immune senescence.

We show in experimental mouse models that the degree of mouse CMV (MCMV)-specific memory CD8+ T cell accumulation and the phenotypic T cell profile are directly influenced by the infectious dose, and data on HCMV-specific T cells indicate a similar connection. Detailed cluster analysis of the memory CD8+ T cell development showed that high-dose infection causes a differentiation pathway that progresses faster throughout the life span of the host, suggesting a virus-host balance that is influenced by aging and infectious dose.

Importantly, short-term MCMV infection in adult mice is not disadvantageous for heterologous superinfection with lymphocytic choriomeningitis virus (LCMV). However, following long-term CMV infection the strength of the CD8+ T cell immunity to LCMV superinfection was affected by the initial CMV infectious dose, wherein a high infectious dose was found to be a prerequisite for impaired heterologous immunity. Altogether our results underscore the importance of stratification based on the size and differentiation of the CMV-specific memory T cell pools for the impact on immune senescence, and indicate that reduction of the latent/lytic viral load can be beneficial to diminish CMV-associated immune senescence.

"We show that Sirt4 is responsible for regulating both lifespan and metabolism in an organism, and specifically that it coordinates the metabolic response to fasting. We also demonstrate that overexpressing the gene for Sirt4 can extend lifespan of the fly." The results suggest that boosting Sirt4 activity may be an important avenue for treating age-related metabolic decline and disorders, such as diabetes and obesity, and promoting a healthy lifespan.

In the study, flies modified to produce extra Sirt4 saw their healthy lifespans extended by 20 percent. Removing the ability of flies to produce Sirt4 cut their healthy lives by 20 percent. Also, without Sirt4 in their cells, flies when removed from food died rapidly, even when nutrients and fats were still present in their bodies. Sirt4 belongs to a class of proteins, called sirtuins, known to regulate aspects of longevity, metabolism, genome stability, diabetes and neurodegeneration. Sirt4 is found in mitochondria, which are cellular structures where respiration and energy production take place.

Human cells contain seven different sirtuins, including three mitochondrial sirtuins, Sirt3, Sirt4 and Sirt5. Fruit fly cells contain just one mitochondrial sirtuin, Sirt 4. Increasing or decreasing expression of Sirt4 in living flies allowed the researchers to discover what function Sirt4 played in the insects - and possibly in humans. "We show for the first time that increasing the activity of a mitochondrial sirtuin can extend lifespan. No previous research has found that increasing the activity of a mitochondrial sirtuin such as Sirt4 extends the healthy lifespan of a living organism."

The study also shows Sirt4 may be a gene responsible for the metabolic action of fasting, particularly the gene vital to regulating when an organism switches from carbs to fat. A creature that lacks the gene starves to death much more rapidly than normal under poor nutritional conditions. Without Sirt4, the fly cannot access many of the nutrients and stored fats when fasting. Researchers know that temporary fasting in a living organism is valuable in resetting its metabolism. Such findings gave rise to what are called "near-starvation" diets to improve health and extend lifespan. But scientists don't know how that fasting-to-reverse-aging mechanism works. Sirtuins likely play a role. "We want to understand more about the role of sirtuins and their involvement in pathways of calorie restriction."

Adipose tissue inflammation is a hallmark characteristic of obesity. Macrophages that infiltrate into adipose tissue and polarize to pro-inflammatory phenotype play a key role in obesity-associated adipose tissue inflammation and insulin resistance. Mechanistically, macrophages activated with the elevation of lipopolysaccharide (LPS) and IFNγ in obesity acquire an inflammatory M1 phenotype, characterized by increased production of pro-inflammatory cytokines and reactive oxygen species (ROS). These cytokines and ROS target adipocytes to further exacerbate adipose tissue inflammation and dysfunction.

Guanylate binding protein 1 (Gbp1) is a GTPase critical for innate immunity. This has been attributed to the role of Gbp1 in transporting autophagic machinery to the pathogen containing vacuoles (PCVs). Gbp1 expression can be largely induced by IFNγ in macrophages. Most previous studies primarily focused on the role of Gbp1 in regulating innate immunity of macrophages to defend against pathogen infections. Little is known about the involvement of Gbp1 in regulating polarization, metabolic programing, and cellular aging of macrophages.

In this study, we tested the hypothesis that Gbp1 plays a role in regulating immunometabolism and senescence of macrophages. We found that Gbp1 was mainly expressed in macrophages, but not adipocytes in response to IFNγ/LPS stimulation; Gbp1 expression was significantly decreased in inguinal white adipose tissue (iWAT) of high-fat diet (HFD)-fed and aged mice. We also observed that downregulation of Gbp1 in macrophages resulted in M1 polarization and impairment of mitochondrial respiratory function possibly via disrupting mitophagy activity. Moreover, macrophages with downregulated Gbp1 displayed dampened glycolysis and exhibited senescence-associated secretory phenotype (SASP). These observations suggest that Gbp1 may play an important role in protecting against mitochondrial dysfunction and preserving immune function of macrophages during aging.

In 1916, researchers demonstrated that lower temperatures could dramatically extend the lifespan of the fruit fly, Drosophila. Other poikilothermic animals, whose internal temperature varies considerably, including C. elegans, also present increased lifespan upon modest temperature reduction. Additionally, lowering the core body temperature of homeothermic animals, such as mice, also increases lifespan, highlighting a general role of temperature reduction in lifespan extension in both poikilotherms and homeotherms. Reduction in core body temperature has been proposed to mediate the longevity benefits of dietary restriction. Conversely, raising the culturing temperature (e.g., to 25°C) greatly shortens nematode lifespan.

How is the cold-dependent lifespan extension mediated? One prominent model assumes that lowering the body temperature would reduce the rate of chemical reactions, thereby leading to a slower pace of living. This model suggests that the extended lifespan observed at low temperatures is simply a passive thermodynamic process. However, a more attractive hypothesis suggests that specific genetic programs might be engaged to actively promote longevity at cold temperatures, as observed upon dietary restriction or other paradigms.

Researchers reasoned that a cold sensor of the TRP channel family might be recruited in this process. The best-known mammalian cold sensors are TRPA1 and TRPM8; however, TRPM8 does not have a C. elegans homolog, thus ruling this receptor out of the candidate-based approach. But, TRPA1 has one ortholog in C. elegans referred to as TRPA-1, which becomes active under 20°C and therefore constitutes an attractive candidate to mediate the longevity extension observed under cold temperature.

Three temperatures (15°C, 20°C, and 25°C) are common laboratory conditions for culturing worms. If TRPA-1 is involved in promoting longevity at low temperatures, one would expect that mutant worms lacking TRPA-1 should have a shorter lifespan at 15°C and 20°C than wild-type worms, but not at 25°C. This is because this cold-sensitive channel is expected to be functional at 15°C and 20°C but remains closed at 25°C. Consistent with this prediction, trpa-1 null mutant worms showed a significantly shorter lifespan than wild-type worms at 15°C and 20°C but not 25°C. Similarly, transgenic expression of TRPA-1 under its own promoter increased lifespan at 15°C and 20°C but not at 25°C.

The ability to affect aging by manipulation of TRP channels in invertebrate models such as C. elegans provides evidence for evolutionary conservation and argues for the investigation of homologous and analogous circuits in mammalian models. Recently, evidence of the conserved function of chemosensory neurons in the regulation of longevity has been provided through the study of the capsaicin receptor TRPV1.

Impairment of TRPV1 sensory receptors is sufficient to extend mouse lifespan and improve many aspects of health in aging mice. Under normal fed ad libitum conditions, the TRPV1 mutation is not sex specific in its effects: longevity in both genders was extended to a similar extent, with 11.9% increase in male TRPV1 mutants and 15.9% increase in median female lifespan compared to wild-type controls. The longevity increase observed in these animals is not due to previously established mouse longevity paradigms such as reduced growth hormone (GH) and/or insulin growth factor (IGF-1) signaling. TRPV1 mutants show no growth delay and do not differ in body composition compared to control animals. TRPV1 mutant mice also do not present core body temperature differences with controls, arguing that their long lifespan is not due to a dietary restriction mimetic mechanism. How can a mutation in a sensory TRPV result in increased lifespan? TRPV1 mutation results in enhanced insulin secretion with age and a youthful metabolic profile that leads to increased lifespan in mice.

Increases in human life expectancy have slowed dramatically across the world since 1950, according to a new study. Although a "ceiling effect" is expected as average lifespan approaches its biological limit, the study found that the trend towards slower gains - and even declines - in lifespan is worst among low-lifespan countries. "This is not about us hitting the ceiling; the slowdown has been sharpest in countries that have the most life expectancy to gain. It's a rebuke to the idea that you can fix global health just by inventing more stuff. New health technology has been essential to making strides in life expectancy, of course, but our predecessors in the 1950s were making faster progress with the basics of soap, sanitation and public health."

Researchers examined life expectancy data for 139 countries and for each one calculated the "decadal" life expectancy gain - the gain from a given year to a decade later - during the period 1950-2009. The analysis revealed that for the total sample, the mean decadal gain started at an impressive 9.7 years during the 1950s but fell more or less steadily to just 1.9 years during the 2000s. The study did not break down data by country or region. The researchers stratified the countries in the sample by their life expectancies, and found that the highest lifespan countries, with life expectancies at birth of at least 71 years, declined from a mean decadal gain of 4.8 years in the 1950s to 2.4 years in 2000-2010. That result was unsurprising, given that life expectancies in these countries are approaching the maximum lifespan of 71-83 years.

However, the researchers found an even steeper decline in countries in the lowest stratum of lifespan, with life expectancies under 51 years. For countries in this category the mean decadal change in life expectancy dropped continuously from a promising gain of 7.4 years in the 1950s to a worrisome loss of 6.8 years in the 2000s. In other words, the low-lifespan countries on average went from experiencing big gains to sharp declines in life expectancy. The HIV/AIDS pandemic, which generally hit hardest in low-lifespan countries, is a factor in this trend but doesn't fully explain it. "The slowdown in life expectancy gains started before AIDS hit in the 1980s and 90s and occurred even in regions that did not have big problems with this disease." He suspects that an important driver of the overall trend is a widespread failure of governance. "Nowadays, the countries with persistently low life expectancy are countries that generally are fragile states."

Mechanistic target of rapamycin (mTOR) plays central roles in growth, metabolism, and aging. It acts via two distinct complexes: mTORC1 and mTORC2, defined by Raptor and Rictor, respectively. Rapamycin, an inhibitor of mTOR, inhibits mTORC1, and longer rapamycin treatment also inhibits mTORC2. Rapamycin was the first drug shown to extend longevity in a mammal. The effects of rapamycin on longevity were accounted for by mTORC1 inhibition, whereas information on mTORC2 is generally lacking. However, it seems that many of the negative adverse effects of rapamycin treatment are mediated by inhibition of mTORC2.

Rictor has positive effects on a variety of functions involved in whole-body homeostasis. Although at this time, the role of mTORC2 in the regulation of longevity is uncertain, several lines of evidence imply that mTORC2 may have opposite effects on aging compared with mTORC1. For instance, Rictor loss-of-function mutants in Caenorhabditis elegans had decreased life spans by 24-43% on a standard diet. Interestingly, transcriptional down-regulation of mTORC1 and transcriptional up-regulation of mTORC2 was reported to be associated with human longevity. It is vital to understand how mTORC2 regulates aging in a mammal.

mTORC2 is regulated by growth hormone (GH)-dependent growth factors. GH is essential for growth and metabolism and is involved in the control of aging. It binds and signals through GH receptor (GHR). Therefore, deletion of GHR eliminates GH signaling and its biological functions. GHR-KO (GHR knockout) mice have been a valuable tool to study GH functions, including its relationship to longevity. GHR-KO mice are dwarf, extremely insulin sensitive, and have their life span extended up to 40%. Importantly, compared with their normal littermates, GHR-KO and several other long-lived mice have decreased mTORC1 and increased mTORC2 signaling, which may play a role in their extended longevity. Therefore, we decided to examine how prolonged rapamycin treatment alters mTORC1 and mTORC2 signaling in GHR-KO mice.

In long-lived GHR-KO mice, prolonged rapamycin treatment did not further extend, but unexpectedly shortened, life span. One possible reason could be that prolonged rapamycin treatment further decreases the already low levels of mTORC1 signaling in these animals, which could adversely affect the benefits of mTORC1 inhibition. However, mTORC1 signaling was not further reduced in three key metabolic tissues of GHR-KO mice with prolonged rapamycin treatment compared with control GHR-KO mice. We cannot explain why prolonged rapamycin treatment did not further decrease mTORC1 signaling in these animals, and also cannot rule out the possibility that mTORC1 signaling may have been further reduced in other tissues.

In contrast, a significant reduction of mTORC2 signaling was evident in each of the examined tissues of GHR-KO mice treated with rapamycin. Decreased mTORC2 signaling and impaired whole-body homeostasis (which could result from reduced mTORC2 signaling) in rapamycin-treated GHR-KO mice might have contributed to the effect of prolonged rapamycin treatment on the life span of GHR-KO mice. Thus, our data indicated that mTORC2 may play a beneficial role in longevity via improving or maintaining whole-body homeostasis. Based on our data and data from previous studies, we propose the following concept: if whole-body homeostasis is impaired (which was associated with the significant reduction of mTORC2 in our study), life span could be shortened, and if mTORC2 signaling is unaltered or enhanced, inhibition of mTORC1 will lead to extension of life span. The effects of altered mTOR signaling on longevity would thus reflect a balance between inhibition of mTORC1 and enhancement, or maintenance, of mTORC2.

Neuroscientists are taking an innovative approach to battling neurodegenerative diseases like Alzheimer's disease and dementia. Rather than trying to understand the specific mechanisms that cause each disease, they took a step back and asked, "What do all these conditions have in common?" The answer: old age. Over time, something happens to our cells and organs, and in the past three decades scientists have begun to unravel exactly what that something is - and the cellular mechanisms our bodies use to fight it.

"Aging is the biggest risk factor for cognitive problems, and cognitive problems are one of the biggest biomedical challenges that we face. Why don't we just block aging?" Blocking aging is easier said than done, but researchers jumped head first into the problem by studying a protein called klotho. The researchers who named the protein found that the amount of klotho produced by mice could affect how long the rodents lived. Other researchers later discovered that humans who naturally have more klotho tend to live longer. Living longer is one thing, but the researchers wanted to know if klotho could help our brains stay healthier and more resilient to cognitive problems. Could klotho levels predict how quickly subjects solved a variety of puzzles that test cognition? In both humans and mice, they found the same result: more klotho meant better cognitive function. To bring this boost in brain health to everyone, and not just the 20 percent of people who happen to have naturally high klotho, researchers are testing the protein's potential as a therapeutic.

The protein can exist in two forms: the first is anchored to the cell membranes of your organs, mostly your brain and kidneys; and the second occurs when the protein is cut loose from its anchor and freed to float around the bloodstream. Researchers found that by simply injecting this floating form into mice, they could re-create the cognitive boost found by genetically increasing klotho. "We found that those mice that had been treated, within four hours had better brain function. This worked in young mice, old mice, and mice that had a condition similar to Alzheimer's. Next, researchers will try to understand how klotho acts on the brain without crossing the blood-brain barrier. And ultimately, could klotho become a therapy for humans to improve brain health and protect against aging and disease? "For humans, the end game really is: how can we increase our healthspan? And that may go hand in hand with an increase in life span, because the things that help us to live longer are also the things that help us to live better."

What impact will your work have on aging research?

I'm studying whether we can separate the process of functional reprogramming of cells from the process of aging reprogramming of cells. Typically these two processes happen at the same time. My hypothesis is that we can induce cellular rejuvenation without changing the function of the cells. If we can manage to do this, we could start thinking about a way to stall aging.

What is the difference between functional and aging reprogramming?

The function of a skin cell is to express certain proteins, keratins for example that protect the skin. The function of a liver cell is to metabolize. Those are cell-specific functions. Reprogramming that function means that you no longer have a liver cell. You now have another cell, which has a totally different function. Age, on the other hand, is just the degree of usefulness of that cell, and it's mostly an epigenetic process. A young keratinocyte cell is younger than an older keratinocyte but it is still a keratinocyte. The amazing thing is that if you take an aged cell that is fully committed to a certain function, and you transplant its nucleus into an immature egg cell called an oocyte, then you revert its function to a pluripotent, embryonic one, which means it can become any other cell of the body-and you also revert the age of that cell to the youngest age possible. It's mind-blowing to me.

How close are we to using pluripotency induction in therapies?

The production of induced pluripotent stem (iPS) cells in mice was described in 2006, and in humans in 2007, so it's been already 10 or 11 years. The first clinical trials using iPS cells are just about to get to early phase I and phase II. There has been a lot of hope and promise but it's been a little slow. The reason being that when it comes to clinical applications, you have to consider a number of complications. You need to know how to make the cells very efficiently, and then they need to be safe. There will be more clinical trials coming up based off iPSs. For example, I am collaborating with an iPS-based platform for the cure of a skin disease called epidermolysis bullosa. We're trying to move this to the pre-clinical stage over the next few years, and then if we pass that, we will potentially start moving into a phase I clinical trial. Things are moving forward pretty fast now.

Are germ cells immune to aging?

Yes and no. They definitely do age, but not to the same extent as other cell types. In males, spermatogenesis continues all the way from puberty to old life. If you take a 90-year-old man, there are still germ cells and spermatogonial stem cells. They do age, because it's clear that the sperm of an older man is different from the sperm of a younger man, but they do not age as heavily as other cells. This is fascinating because we do not understand the process. Female cells do age, and the consensus is that there are no germ stem cells in the ovary so these cells lack a molecular program to stay young. But once you put together an egg and a sperm, then there is an aging erasure mechanism, which is embryonic-specific, that we also do not understand.

Why are you interested in separating aging reprogramming from functional reprogramming?

The experiments of somatic cell nuclear transfer and iPS cell derivation clearly indicate that both functional and aging reprogramming can be achieved. However, these technologies are very inefficient and cannot be used as whole-body anti-aging measures because the process of reprogramming to an embryonic stage can lead to tumorigenic cells. Instead, if we could separate the two types of reprogramming and achieve only reprogramming of age without touching the function of a cell, then in principle we could apply reprogramming in vivo to every single cell in the body and rejuvenate them. This could be a paradigm shift in the way we approach aging.

Injecting minute amounts of two immune-stimulating agents directly into solid tumors in mice can eliminate all traces of cancer in the animals, including distant, untreated metastases. The approach works for many different types of cancers, including those that arise spontaneously. The researchers believe the local application of very small amounts of the agents could serve as a rapid and relatively inexpensive cancer therapy that is unlikely to cause the adverse side effects often seen with bodywide immune stimulation.

Some immunotherapy approaches rely on stimulating the immune system throughout the body. Others target naturally occurring checkpoints that limit the anti-cancer activity of immune cells. Still others, like the CAR T-cell therapy recently approved to treat some types of leukemia and lymphomas, require a patient's immune cells to be removed from the body and genetically engineered to attack the tumor cells. Many of these approaches have been successful, but they each have downsides - from difficult-to-handle side effects to high-cost and lengthy preparation or treatment times. Cancers often exist in a strange kind of limbo with regard to the immune system. Immune cells like T cells recognize the abnormal proteins often present on cancer cells and infiltrate to attack the tumor. However, as the tumor grows, it often devises ways to suppress the activity of the T cells.

The new method works to reactivate the cancer-specific T cells by injecting microgram amounts of two agents directly into the tumor site. One, a short stretch of DNA called a CpG oligonucleotide, works with other nearby immune cells to amplify the expression of an activating receptor called OX40 on the surface of the T cells. The other, an antibody that binds to OX40, activates the T cells to lead the charge against the cancer cells. Because the two agents are injected directly into the tumor, only T cells that have infiltrated it are activated. In effect, these T cells are "prescreened" by the body to recognize only cancer-specific proteins. Some of these tumor-specific, activated T cells then leave the original tumor to find and destroy other identical tumors throughout the body.

The approach worked startlingly well in laboratory mice with transplanted mouse lymphoma tumors in two sites on their bodies. Injecting one tumor site with the two agents caused the regression not just of the treated tumor, but also of the second, untreated tumor. In this way, 87 of 90 mice were cured of the cancer. Although the cancer recurred in three of the mice, the tumors again regressed after a second treatment. The researchers saw similar results in mice bearing breast, colon and melanoma tumors. "This is a very targeted approach. Only the tumor that shares the protein targets displayed by the treated site is affected. We're attacking specific targets without having to identify exactly what proteins the T cells are recognizing."