Early-stage research has shown that cancer cells from a well-known human cancer cell line (HeLa cells) can be killed by human neutrophils (a type of innate immune cell) that have been produced in a laboratory rather than in the body. The research opens up the possibility of being able to give patients access to the kind of exceptional cancer killing abilities that the immune cells of some healthy people naturally have. The work means that LIfT BioSciences, the company behind the work, can now proceed with their mission to create the world's first cell bank of cancer killing immune cells that forms the basis for their potentially curative Leukocyte Infusion Therapy (LIfT).

The work was achieved in partnership with King's College London. Professor Farzin Farzaneh, who is leading the research at King's, commented, "I was initially sceptical about this when LIfT Biosciences approached us. It is something that I don't believe has been done before, and producing these specific cells with cancer killing ability is a notion we had not thought of before. We are excited by these early results and see the potential in LIfT BioSciences' approach for further work". LIfT BioSciences are partnered with King's College London by life sciences cluster organisation, MedCity, after being selected for their 'Collaborate to Innovate' programme.

The breakthrough in the production of cancer-killing immune cells in the laboratory means that LIfT BioSciences's special cells can now potentially be produced in very high volumes without the need for repeated blood donations. LIfT's Prof Zheng Cui discovered over a decade ago that certain individuals naturally have white blood cells with exceptional cancer-killing abilities, which can potentially be transfused into cancer patients. However, until now this was not logistically considered a realistic therapy for the global fight against cancer. Previously, to provide a sufficiently therapeutic volume of these cells would have required the screening of hundreds, or even thousands of donors in order to treat one patient. This new, patent pending invention potentially provides a viable, scalable, and safe method of producing a sufficient number of effective cancer-killing cells for treating cancer patients.

The breakthrough also firmly positions LIfT as a product therapy rather than a medical procedure which means accelerated access to market and patients. Further research to enhance the cancer-killing activity of these neutrophils will confirm the Advanced Therapeutic Medicinal Product (ATMP) status which was awarded to LIfT by the European Medicines Agency earlier this year.

Some individuals' skin appears more youthful than their chronologic age. New research indicates that increased expression of certain genes may be the key to intrinsically younger looking - and younger behaving - skin. "It's not just the genes you are born with, but which ones turn on and off over time. We found a wide range of processes in the skin affected by aging, and we discovered specific gene expression patterns in women who appear younger than their chronologic age."

To produce a comprehensive model of aging skin, researchers collected and integrated data at the molecular, cellular, and tissue levels from the sun-exposed skin (face and forearm) and sun-protected skin (buttocks) of 158 white women ages 20 to 74 years. As part of the study, the team looked for gene expression patterns common in women who appeared years younger than their chronologic age. The physical appearance of facial skin was captured through digital images and analysis. Skin samples were processed for analysis and saliva samples were collected for genotyping. The analyses revealed progressive changes from the 20s to the 70s in pathways related to oxidative stress, energy metabolism, cellular senescence, and skin barrier. These changes were accelerated in the 60s and 70s. Comparing sun-exposed and sun-protected skin samples revealed that certain genetic changes are likely due to photoaging.

The gene expression patterns from the women in the study who were younger appearing were similar to those in women who were actually younger in age. These women had increased activity in genes associated with basic biologic processes, including DNA repair, cell replication, response to oxidative stress, and protein metabolism. Women with exceptionally youthful-appearing facial skin in older age groups also had higher expression of genes associated with mitochondrial structure and metabolism, overall epidermal structure, and barrier function in their facial epidermal samples, as well as dermal matrix production.

Gene expression and ontology analysis of photoexposed and photoprotected skin samples in Caucasian women across 6 decades revealed progressive, age-related changes from their 20s to their 70s. All these aging processes accelerated in the 60s and 70s, co-occurring with menopause. Histologic elastosis was apparent in photoexposed sites (face and dorsal forearm) beginning in the 40-year-old cohort, suggesting that earlier molecular processes are important precursors to what later becomes histologically and clinically apparent changes in skin appearance. The results demonstrate that younger-looking skin in older cohort groups shows gene expression patterns that mimic chronologically younger skin on a molecular level. This finding offers the potential for future inquiry into biologic factors that slow evolution of aging processes.

Genes related to DNA repair and replication, cell growth and survival, chromatin remodeling, response to oxidative stress, autophagy, and protein metabolism are expressed differently in youthful skin than in older-appearing skin. In addition, epidermal structure and barrier, as well as dermal matrix, are also better maintained in youthful-appearing skin, with increased expression of genes such as CDH1, DSC3, and LAMA5 likely contributing. CDH1 and DSC3 are components of cell-cell junctions in the epidermis, and LAMA5 is essential for attachment of keratinocytes to the basement membrane. Expression of these three genes was significantly increased in youthful-appearing skin, intermediate in average-appearing skin, and decreased in older-appearing skin.

In addition, dermal genes associated primarily with extracellular matrix structure were differentially expressed depending on appearance of the facial skin. Genes associated with cellular metabolism also decreased more markedly with age in the epidermis of older- than younger- or average-appearing facial skin. This pattern mirrored individual genes representing examples of different processes related to mitochondrial structure and metabolism. A decrease in cellular energy metabolism has previously been linked to visible signs of skin aging such as wrinkling.

Cell senescence, indicated by CDKN2A expression, increased markedly in the photoexposed arm and facial skin, particularly in the epidermis. CDKN2A codes for multiple proteins including p16INK4a, which is associated with suppression of cell replication and induction of cellular senescence - key causes of aging. Even small fractions of senescent cells can contribute to visible aging and underlying processes, including inflammation in photoexposed skin sites. Increased CDKN2A expression corresponded with sun exposure and aged appearance of facial skin.

In summary, genetics play a fundamental role in setting the pathways of aging, but how aging occurs is associated with changes in expression of these genes over time. Genes associated with youthful-appearing skin represent fundamental cellular repair and metabolic processes, as well as functional properties such as skin barrier. Furthermore, the observed differences in onset and time progression of changes in gene expression across key aging pathways might present interesting biomarkers and targets to provide further insights into skin aging.

The costs of dementia are enormous and increasing globally. Current clinical guidelines for dementia prevention view obesity as one of the modifiable risk factors, but the evidence is based on a relatively limited number of observational studies and the findings are mixed. The most recent meta-analysis, including 4 studies and 16,282 participants, suggested a 1.4-fold increased risk of dementia in the obese. The largest study in the field, published after the inclusion date for the meta-analysis, found no increase in dementia incidence among the obese. On the contrary, higher body mass index (BMI) was linked to lower dementia risk. The reasons for this discordance in findings are unclear.

One possibility is that the observed association between BMI and dementia is attributable to two processes: one is a direct association between higher BMI and increased dementia risk, and the other is an association confounded by weight loss during the preclinical dementia phase, which leads a harmful exposure to appear protective via reverse causation. This hypothesis is supported by the fact that clinical diagnosis of dementia is often preceded by a long (20-30 years) preclinical phase during which cardiometabolic changes, including weight loss, are common. Thus, lower BMI close to dementia onset might be a consequence of preclinical disease rather than a cause of dementia.

The purpose of the present analyses was to investigate the BMI-dementia association using raw unpublished data. We included 39 prospective cohort studies which comprised a total of 1,349,857 participants with no history of dementia; were population based with BMI assessed from all participants before the ascertainment of dementia; recorded hospital-treated dementia or dementia deaths; and had accrued a minimum of 3 years of follow-up. We found that higher BMI was associated with increased dementia risk when weight was measured more than 20 years before dementia diagnosis, but this association was reversed when BMI was assessed less than 10 years before dementia diagnosis. The findings of this study are consistent with the hypothesis that the BMI-dementia association is attributable to two processes: a direct (causal) effect and reverse causation as a result of weight loss during the preclinical dementia phase.

As the present meta-analysis is based on a series of studies in which investigators ascertained dementia in different ways, we had the possibility to undertake a validation exercise. Thus, we repeated the main analyses excluding dementia status drawn from death certificates. The same pattern of results was evident as in the main analyses: higher BMI was associated with greater risk of dementia when BMI was measured many years before dementia onset, whereas an inverse relationship was apparent when BMI was measured closer to dementia ascertainment.

In analyses exploring survival bias, we found that higher baseline BMI was associated with an increased risk of all-cause mortality before the age of 65 years but lower mortality risk after the age of 85 years (the median age of dementia diagnosis). These findings suggest that, compared with their normal weight counterparts, obese individuals were less likely to live long enough to develop dementia and more likely to die from conditions that are known to be related to increased dementia risk, such as diabetes and cardiovascular diseases. Given these findings, differences in survival may have contributed, if anything, to an underestimation of the strength of the association between BMI and dementia.

Skin acts as a mirror to the internal state of the body. There are many scoring systems used in the assessment of skin aging. SCINEXA (SCore for INtrinsic and EXtrinsic skin Aging) is an easy-to-use clinical scoring system recently developed to differentiate between chronological (intrinsic) skin aging and photo (extrinsic) skin aging. However, no studies have evaluated the relationship between skin-aging parameters and the incidence of degenerative advanced-degree atrioventricular conduction disorders, or AV block. With increasing age, these disorders are inevitable. About 30% of people older than 65 years have AV conduction or intraventricular conduction defects. Pulse rate interval increases with increasing age caused by delayed conduction in the atrioventricular node (AVN) and the proximal portion of the His bundle.

Can we use skin parameters to predict the presence of heart block? Carotid atherosclerosis is related to perceived age (associated with higher degrees of facial pigmentation), and may be a better predictor of mortality than chronological age. In our study, uneven pigmentation was higher in those with advanced-degree heart block; the grades of fine skin wrinkles were significantly higher in heart block group.

Our skin becomes stiff, thin, and flabby, with the development of more wrinkles with advanced age, and all are related to fibrosis of the skin, as elastic fibers are injured and collagen fibers are broken with the passage of time. New collagen fibers are produced to replace broken elastic fibers and broken collagen fibers. Tissue fibrosis due to progressive deposition of excessive collagen fibers has been observed in most organs with aging, especially the heart. This results in hardening and atrophy of that organ, secondary to loss of parenchyma cells and the increase of collagen substance in tissues. Essential arterial hypertension, sinus node dysfunction, and degenerative AV block are examples of cardiac complications that are caused by tissue fibrosis. In our study, the grades of the lax appearance of the face and reduced fat tissue, prevalence of seborrheic keratosis, and the total score of intrinsic skin aging were significantly higher in the group of heart block.

The association between intrinsic skin aging and degenerative advanced-degree AV block could be explained by the pathogenesis background that may be incriminated in the development of both disorders. Extensive evidence, derived from both clinical and experimental studies, suggests that the aging heart undergoes fibrotic remodeling. Advanced glycation end products (AGEs), which are developed by the glycation and oxidation of different structural proteins, and play an important role in age-dependent changes, were described in skin aging and in organs such as the kidney, blood vessels, and the eye lenses. AGEs are important factors for assessing cardiac aging and fibrosis. Further, diminished expression of connective tissue growth factor (CTGF) is responsible for the progressive loss of dermal collagen. There are positive correlations between the levels of CTGF and cardiovascular fibrotic diseases in the elderly population.

The progressive increase in blood pressure (BP) with age is characterized by a greater increase in isolated systolic hypertension, a larger elevation in systolic blood pressure (SBP) than diastolic blood pressure (DBP), leading to an accelerating rise in pulse pressure (PP). Although it is widely accepted that the increase in SBP with advancing age is mostly consistent with the large artery stiffening, there is still no consensus on what are the primary causes of these disorders. Our recent studies show that increased intrinsic stiffness of vascular smooth muscle cells (VSMCs) in aorta is an important contributor to the pathogenesis of aortic stiffening in both aging and hypertension, and that this could be a novel target for future anti-aortic stiffness drug development. However, less is known about molecular regulation involved in the VSMC stiffening in large arteries.

Rho-associated protein kinase (ROCK) is a serine/threonine protein kinase that has been identified as one of the effector of the small GTP-binding protein Rho. Although accumulating evidence has demonstrated that the ROCK pathway plays a crucial role in the pathogenesis of hypertension, ROCK has not previously been shown to be involved in cellular stiffening of VSMC. Inhibition of ROCK significantly reduced blood pressure in human and animal models of hypertension, despite the precise molecular mechanism underling the anti-hypertensive effect not being fully understood.

Thus, we hypothesize that ROCK participates in the regulation of aortic stiffness via altering VSMC stiffness in hypertension. In this study, we integrated atomic force microscopy (AFM) and molecular approaches to determine whether increased stiffness of aortic VSMCs in hypertensive rats is ROCK-dependent, and whether the anti-hypertensive effect of ROCK inhibitors contributes to the reduction of aortic stiffness via changing VSMC mechanical properties.

Despite a widely held belief that aortic stiffening is associated with changes in extracellular matrix proteins and endothelial dysfunction, our recent studies demonstrated that intrinsic stiffening of aortic VSMCs, independent of VSMC proliferation and migration, is an important contributor to aortic wall stiffening both in hypertensive and aged animals. The present study demonstrates for the first time that ROCK is a novel mediator of aortic VSMC stiffening in hypertension, which has never been described previously. Furthermore, our study also indicated that attenuation of aortic VSMC stiffening by pharmacological inhibition can serve as a promising therapeutic target to correct aortic stiffening not only in hypertension, but also in other age-related vascular diseases.

The endogenous protein RAGE, which has usually been negatively associated with chronic inflammation and diabetic complications, plays a major role in the repair of DNA damage - and also appears to heal tissue damaged as a result of accelerated cell senescence. Researchers discovered the potential therapeutic benefit of the protein in mice that are unable to produce RAGE. As a result of the limited DNA repair, they develop pronounced pulmonary fibrosis, i.e. scarring in the lungs. After treatment with the protein, the scarring healed. "This is astonishing in that fibrosis has so far been considered irreversible. With RAGE, we could for the first time have found a possible starting point to cure this frequent tissue damage. Many questions - e. g. how this healing works in detail - are still unanswered."

RAGE (Receptor of Advanced Glycation Endproducts) is well known in medical research. The protein plays a decisive role not only in diabetes but also in chronic and excessive inflammatory reactions such as atherosclerosis and sepsis, but also in Alzheimer's disease and cancer development. The protein is mainly active on the surfaces of tissue cells and cells of the immune system. On the other hand, inside the cells, to be more precise in the cell nucleus, RAGE shows a completely different side of itself: Here it is responsible for the error-free repair of severe DNA damage, known as double-strand breaks. In these cases of damage, the two interconnected and twisted strands of DNA are completely cut off. Without immediate repair, the cell would quickly perish.

Mice that are unable to form RAGE due to a genetic defect will develop pulmonary fibrosis. The lungs are particularly susceptible to tissue damage, as they are in constant contact with the outside world through the air they breathe and are particularly exposed to environmental influences. In the animal model, the researchers succeeded in elucidating the hitherto unknown molecular mechanism of DNA repair under RAGE involvement and in identifying further important protagonists. If they introduced RAGE into the mice's lungs with the help of modified viruses, it was not only DNA repair that normalized: To the scientists' surprise, the scarred tissue regenerated and regained some of its functionality.

"The development of cancer cells triggers the generation of SOS molecules recognized by the body's scavenger cells, called macrophages. However, aggressive cancers express a 'don't eat me' signal in the form of CD47 on their surfaces. Now we've identified a second 'don't eat me' signal and its complementary receptor on macrophages. We've also shown that we can overcome this signal with specific antibodies and restore the ability of macrophages to kill the cancer cells. Simultaneously blocking both these pathways in mice resulted in the infiltration of the tumor with many types of immune cells and significantly promoted tumor clearance, resulting in smaller tumors overall. We are excited about the possibility of a double- or perhaps even triple-pronged therapy in humans in which we combine multiple blockades to cancer growth."

Macrophages are large white blood cells found in nearly all the body's tissues. As part of what's known as the innate immune system, they engulf and kill foreign invaders like bacteria or viruses. They also destroy dead and dying cells and, in some cases, cancer cells whose internal development cues have gone haywire. The newly discovered binding interaction used by cancer cells to evade macrophages capitalizes on a protein structure on the cancer cells' surface called the major histocompatibility complex class 1, or MHC class 1. Human tumors that have high levels of MHC class 1 on their surfaces are more resistant to anti-CD47 treatment than are those with lower levels of the complex, the researchers found.

MHC class 1 is an important component of adaptive immunity. Most cells of the body express MHC class 1 on their surfaces as a way to indiscriminately display bits of many proteins found within the cell - a kind of random sampling of a cell's innards that provides a window into its health and function. If the protein bits, called peptides, displayed by the MHC are abnormal, a T cell destroys the cell. Although the relationship between MHC class 1 and T cells has been well-established, it's been unclear whether and how the complex interacts with macrophages.

Researchers found that a protein called LILRB1 on the surface of macrophages binds to a portion of MHC class 1 on cancer cells that is widely shared across individuals. This binding inhibits the ability of macrophages to engulf and kill the cancer cells, both when growing in a laboratory dish and in mice with human tumors, the researchers found. Understanding the balance between adaptive and innate immunity is important in cancer immunotherapy. For example, it's not uncommon for human cancer cells to reduce the levels of MHC class 1 on their surfaces to escape destruction by T cells. People with these types of tumors may be poor candidates for cancer immunotherapies meant to stimulate T cell activity against the cancer. But these cells may then be particularly vulnerable to anti-CD47 treatment, the researchers believe. Conversely, cancer cells with robust MHC class 1 on their surfaces may be less susceptible to anti-CD47.

Biomedical engineers have created a fully functioning artificial human heart muscle large enough to patch over damage typically seen in patients who have suffered a heart attack. The advance takes a major step toward the end goal of repairing dead heart muscle in human patients. "Right now, virtually all existing therapies are aimed at reducing the symptoms from the damage that's already been done to the heart, but no approaches have been able to replace the muscle that's lost, because once it's dead, it does not grow back on its own. This is a way that we could replace lost muscle with tissue made outside the body."

Unlike some human organs, the heart cannot regenerate itself after a heart attack. The dead muscle is often replaced by scar tissue that can no longer transmit electrical signals or contract, both of which are necessary for smooth and forceful heartbeats. The end result is a disease commonly referred to as heart failure. New therapies are needed to prevent heart failure and its lethal complications. Current clinical trials are testing the tactic of injecting stem cells derived from bone marrow, blood, or the heart itself directly into the affected site in an attempt to replenish some of the damaged muscle. While there do seem to be some positive effects from these treatments, their mechanisms are not fully understood. Fewer than one percent of the injected cells survive and remain in the heart, and even fewer become cardiac muscle cells.

Heart patches, on the other hand, could conceivably be implanted over the dead muscle and remain active for a long time, providing more strength for contractions and a smooth path for the heart's electrical signals to travel through. These patches also secrete enzymes and growth factors that could help recovery of damaged tissue that hasn't yet died. For this approach to work, however, a heart patch must be large enough to cover the affected tissue. It must also be just as strong and electrically active as the native heart tissue, or else the discrepancy could cause deadly arrhythmias. This is the first human heart patch to meet both criteria.

Finding the right combination of cells, support structures, growth factors, nutrients and culture conditions to grow large, fully functional patches of human heart tissue has taken the team years of work. Every container and procedure had to be sized up and engineered from scratch. And the key that brought it all together was a little bit of rocking and swaying. "It turns out that rocking the samples to bathe and splash them to improve nutrient delivery is extremely important. We obtained three-to-five times better results with the rocking cultures compared to our static samples." Tests show that the heart muscle in the patch is fully functional, with electrical, mechanical and structural properties that resemble those of a normal, healthy adult heart.

Researchers have already shown that these cardiac patches survive, become vascularized and maintain their function when implanted onto mouse and rat hearts. For a heart patch to ever actually replace the work of dead cardiac muscle in human patients, however, it would need to be much thicker than the tissue grown in this study. And for patches to be grown that thick, they need to be vascularized so that cells on the interior can receive enough oxygen and nutrients. Even then, researchers would have to figure out how to fully integrate the heart patch with the existing muscle. "We are actively working on that, as are others, but for now, we are thrilled to have the 'size matters' part figured out."

The cellular homeostasis maintains existence of life through integrative communication among various macromolecules working in unity through numerous biochemical pathways. The endoplasmic reticulum (ER) not only maintains Ca2+ homeostasis but also controls translation, folding, maturation, and trafficking of about one third of cellular proteins. Various environmental insults can disturb proper functioning of ER, leading to accumulation of unfolded/misfolded protein cargo in the ER that gives rise to a condition called ER stress. The cell responds through a highly conserved pathway known as the ER unfolded protein response (UPRER). UPRER first focuses on alleviation of the imposed stress by initiating steps of adaptive mechanisms in the secretory pathway for restoration of homeostasis but conditions of prolonged stress and damage provokes a cell into self-destruction through apoptosis.

Aging is notably a process during which the cell witnesses decline in its ability to respond to stress. Age related frailty perturbs the multifarious schematic of UPRER giving rise to a myriad of pathologies characterized by the presence of disease specific misfolded proteins playing havoc with cellular homeostasis. Further, the master transcriptional regulator of inflammation nuclear factor-κB (NF-κB) has been reported to be upregulated during ER stress. UPRER touches inflammatory signaling cascade directly/indirectly through NF-κB.

The process of aging causes decline in the proper functioning of cellular metabolic pathways. The changes in cells undergoing aging weaken UPRER, causing it to fail to recuperate ER stress. The various molecular chaperones in the ER undergo oxidative damage in the aging cell that diminishes the efficiency of these molecular chaperones to fold proteins; hence, presenting a mass of misfolded protein cargo. This causes protein toxicity, leading to derangement in proteostasis, which becomes an underlying cause of age related diseases.

Neurodegenerative diseases find their source of origin in the perturbations that alter proper functioning of ER. Age related frailty disarms the adaptive arm of UPRER and presents distressing conditions in the brain to promote accumulation of misfolded protein cargo in the ER that later on become inclusions of specific abnormal proteins. Most of the models of aging driven neurodegenerative disease have been marked with the presence of specific protein inclusions because of ER stress in the brain and central nervous system, which are toxic to the post-mitotic neurons.

Studies of model organisms have reinforced the importance of the activation of UPRER molecular markers in stimulating longevity. Age related dysfunction in UPRER promotes the accumulation of misfolded protein cargo, which eventually becomes toxic intracellular inclusions. As the prominent aging driven neurodegenerative diseases share a common pathology of toxic misfolded protein accumulations, this provides an opportunity for therapeutic interventions in the UPRER pathway that can stave off both aging and neuropathologies.

By 2030, the US Census Bureau projects that one in five people in the US alone will be over the age of 65, a major risk factor for many of the most prevalent, costly, and devastating diseases of today, including cancer, cardiovascular disease, Alzheimer's disease, and Type II diabetes. To offset the burden of this increase, efforts are underway to develop an anti-aging drug or other geroprotective intervention that could extend healthspan, lower disease rates, and maintain productivity in this age group.

Unfortunately, there are many roadblocks to such an intervention. While many aging mechanisms are now catalogued and hundreds of drugs extend lifespan in animal models, approval and testing of new drugs in humans is slow, expensive, and prone to high failure rates. This is particularly true in longevity research and exacerbated by a lack of reliable aging biomarkers other than disease itself. Even if successful, to be used preventatively, anti-aging drugs face extraordinarily high safety and efficacy standards for approval.

One strategy to hasten the process has been the repurposing of existing, FDA-approved drugs that show off-label anti-cancer and anti-aging potential, and at the top of that list are metformin and rapamycin, two drugs that mimic caloric restriction. Taken together, rapamycin and metformin are promising candidates for life and healthspan extension; however, concerns of adverse side effects have hampered their widescale adoption for this purpose. While short term rapamycin use is considered safe, it has been reported to be associated with adverse events. Metformin, while relatively safe, is poorly tolerated in one fourth to one half of patients due to gastrointestinal side effects.

In this work, we initiate an effort to identify safe, natural alternatives to metformin and rapamycin. Our work is done entirely in silico and entails the use of metformin and rapamycin transcriptional and signaling pathway activation signatures to screen for matches amongst natural compounds. We have shown previously that the transcriptional signature of a given drug response, disease state, or other physiological condition, when mapped to the signal pathway activation signature, can be useful for biomarker development and drug screening. In the present study, we apply these methods to screen for nutraceuticals that mimic metformin and/or rapamycin. We reduce a list of over 800 natural compounds to a shortlist of candidate nutraceuticals that show both similarity to the target drugs and low adverse effects profiles.

Since the dawn of medicine, aging has been doctors' foremost challenge. Three unsuccessful approaches to conquering it have failed: treating components of age-related ill health as curable diseases, extrapolating from differences between species in the rate of aging, and emulating the life extension that famine elicits in short-lived species. SENS Research Foundation is spearheading the fourth age of anti-aging research: the repair of age-related damage, that is, rejuvenation biotechnology. The Strategies for Engineered Negligible Senescence (SENS) approach was first proposed in 2002; we seek methods to convert a population experiencing a non-negligible level of senescence into one experiencing a negligible level.

To see how the goal of negligible senescence could be "engineered," it is useful to consider a situation in which human ingenuity and perseverance has already achieved an analogous result. Motor vehicles experience a process of wear-and-tear essentially similar to organismal aging; the paint flakes, windowpanes chip, rust infiltrates the pipework, and so forth. Nonetheless, as vintage car owners will attest, it is entirely possible to keep one functional for an essentially indefinite period. Critically, this is achieved not by preventing the wear but by repairing the damage that does occur at a rate sufficient to ensure that the function of the machine is never irretrievably compromised.

Aging can be characterized as a three-stage process. In the first stage, metabolic processes essential to life produce toxins. Secondly, a small amount of the damage caused by these toxins cannot be removed by the body's endogenous repair systems, and consequently accumulates over time. In the third stage, the accumulation of damage drives age-related pathology. This model - metabolism causes damage causes pathology - allows us to clarify the requirements for successful intervention in aging. Unlike the dynamic processes of metabolism and pathology, accumulated damage represents a relatively stationary target. That is to say, it may not be clear whether a given type of damage is pathological (on balance), but its absence from healthy twenty-year-olds indicates that it is not required for healthy life. Conversely it is clear that the total ensemble of types of damage in a fifty-year-old is pathological.

Accepting the implications of this model leads us to the SENS approach; by identifying and repairing all of the damage accumulated during aging, we can restore the body to a youthful state. Consequently, its dynamic metabolic processes will revert to their own norms, and the risk of mortality will be no higher than in any other equivalently "youthful" individual - whether they have actually lived for twenty years or 120. Furthermore - so long as our inventory of damage classes is sufficiently comprehensive - we can repeat this effort on a regular basis, and thus remain indefinitely below the threshold of pathology.

SENS is a hugely radical departure from prior themes of biomedical gerontology, involving the bona fide reversal of aging rather than its mere retardation. By virtue of a painstaking process of mutual education between the fields of biogerontology and regenerative medicine, it has now risen to the status of an acknowledged viable option for the eventual medical control of aging and its credibility will continue to rise as the underlying technology of regenerative medicine progresses.

The enzyme - RNA polymerase III (Pol III) - is present in most cells across all animal species, including humans. While it is known to be essential for making proteins and for cell growth, its involvement in ageing was unexplored until now. A study has found that the survival of yeast cells, and the lifespans of flies and worms were extended by an average of 10% following a modest reduction in Pol III activity in adulthood. "We've uncovered a fundamental role for Pol III in adult flies and worms: its activity negatively impacts stem cell function, gut health, and the animal's survival. When we inhibit its activity, we can improve all these. As Pol III has the same structure and function across species, we think its role in mammals, and humans, warrants investigation as it may lead to important therapies."

The effects of inhibiting Pol III were found to be comparable to the action of the immune-suppressing drug rapamycin, which has previously been shown to extend the lifespans of mice and many other animals. This discovery will help scientists understand the mechanism of action of drugs, such as rapamycin, that show promise for extending the lifespans of mammals. "Understandably, there's a lot of hype around drugs that extend lifespan and promote healthy ageing but very little is known about how they work, which is fundamental knowledge. We now think that Pol III promotes growth and accelerates ageing in response to a signal inhibited by rapamycin, and that inhibiting Pol III is sufficient to result in flies living longer as if they were given rapamycin. If we can investigate this mechanism further and across a wider range of species, we can develop targeted antiaging therapies."

Yeast, flies and worms were used as model organisms as they are not closely related but all contain Pol III. Inhibiting Pol III in the guts of flies and worms, was sufficient to extend lifespan, and when Pol III was inhibited in flies' intestinal stem cells alone, they also lived longer. The team now plan on continuing their work on Pol III to understand its function in an adult organism, and hence shed light on how a reduction in its activity can extend lifespan.

A study by researchers reveals that an anti-aging protein can be targeted to rejuvenate cells in the immune system. The protein in question is called SIRT1. The scientists found that it is involved in how cells in the immune system develop with age. They wanted to find out how this anti-aging protein affects a specific category of immune cells known as cytotoxic T cells. These cells are highly specialized guardians of the immune system and their role is to kill cells infected by a virus, damaged cells, or cancer cells.

"Over the course of a person's life, with repeated exposure to bacteria and viruses, these T cells mature and eventually lose a protein called CD28. And as these cells get older, they become more toxic to their environment." This aging process is accelerated by persistent viral infections, such as HIV and cytomegalovirus. In fact, HIV-infected patients accumulate mature cytotoxic T cells at a much younger age than an uninfected person.

When a young (or naive) T cell is in a resting state, it uses oxygen to "breathe". Once it is activated to defend the body against a bacteria or virus, it shifts into enhanced glycolysis and uses sugar to get an immediate boost in energy. This is useful to jump into action, but it isn't sustainable for long-term performance. As the cells age and lose CD28, they can shift into glycolysis much more quickly if breathing is inhibited. They also lose the anti-aging protein SIRT1. This becomes a problem, as it makes them more toxic to the cells around them.

"We studied human T cells, isolated from blood donors of all ages, to compare mature cytotoxic T cells with naive ones." The researchers found that naive T cells have a high concentration of SIRT1. This stabilizes an entire mechanism that prevents the cells from entering glycolysis to use sugar as an energy source, and limits their toxic effects. As the cells age, they lose SIRT1, which changes their basic metabolism. They can then rapidly shift into glycolysis and start producing more toxic proteins called cytokines, which could lead to inflammatory diseases.