Fight Aging! Newsletter, June 6th 2016

June 6th 2016

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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  • The Use of Stem Cell Therapies to Treat Osteoarthritis
  • Recent Research into Blood-Brain Barrier Dysfunction and Alzheimer's Disease
  • A Little More Recent Research on the Topic of Reactive Oxygen Species
  • Undergoing Chemotherapy or Radiotherapy is, Literally, a Damaging Experience, but are These Consequences a Form of Accelerated Aging?
  • Sweat Glands are Essential to Skin Regeneration, but are Sabotaged by Aging
  • Latest Headlines from Fight Aging!
    • Telomere Length Suggested as the Mechanism Limiting Heart Regeneration
    • Reviewing What is Known of FGF23 and Klotho Signaling in Aging
    • Nanoparticles to Target Atherosclerotic Plaques
    • Use of a Fasting-Mimicking Diet to Attenuate Progression of Multiple Sclerosis
    • Bacterial Stimulation of FOXN1 Theorized to Enhance Healthy Longevity
    • The Details Matter for Reactive Oxygen Species in Aging
    • Exploring the Effects of Longer Telomeres without Telomerase Gene Therapy
    • Nanoparticles and RNA Used to Engineer an Immune Response to Cancer
    • Stem Cell Treatments Produce Considerable Benefits in Stroke Survivors
    • Gene Therapy Reprograms Cells to Reduce Liver Fibrosis


Today I'll point out a review paper that covers a few approaches to stem cell therapy in the context of treating osteoarthritis, a degenerative condition of the joints. Arguably the most demonstrably successful branch of stem cell medicine today is that focused on treating the issues that arise in aging joints: deterioration of tissues, wearing of bone and cartilage, and associated inflammation, pain, and loss of function. The methodologies used for mesenchymal stem cell transplants, developed over the past fifteen to twenty years, today have a good expectation of delivering noticeable improvement to patients. A short turnaround to improvement that is self-evident to the patient is an important component for success in medicine. Therapies that deliver only statistical improvements to function and risk of disease without rapid and obvious physiological improvement from the perspective of the patient - and this category still includes many stem cell therapies for internal organ damage at this point - are a much harder sell at all levels of development.

Stem cell activity declines with age, a reaction to growing levels of cell and tissue damage. This decline is thought to trade off risk of death by cancer on the one hand, the result of damaged cells undertaking more activity, with risk of death due to loss of tissue function on the other hand, the result of stem cells becoming less active and thus delivering fewer replacement cells to the tissues they support. Restoring stem cell populations to their youthful undamaged and active state is a necessary component in any future rejuvenation toolkit. Present day stem cell therapies do not achieve this goal, however. They appear to work largely by altering the local signaling environment for a short period of time, putting existing cells back to work, spurring greater regeneration, and reducing inflammation. The transplanted cells in many cases live only a short time. Most stem cell therapies available today should be viewed as a burst of rebuilding, but rebuilding that uses damaged tools and damaged materials. Nonetheless, even though this is compensation, not rejuvenation, it can result in significantly better patient outcomes than the other presently available options.

Mesenchymal stem cell therapy in the treatment of osteoarthritis: reparative pathways, safety and efficacy - a review

Osteoarthritis (OA) is a major cause of disability and chronic pain, characterized by progressive and irreversible cartilage degeneration. The capacity of articular cartilage to repair is inherently poor, with the relative avascularity of cartilage, and hence lack of systemic regulation, likely leading to an ineffective healing and reparative response. With advances in modern medicine improving the prevention, diagnosis and treatment of many diseases that were once life-threatening, the population is now living longer. This increased life expectancy has led to an increased burden of degenerative conditions including osteoarthritis. Current medical treatment strategies for OA are aimed at pain reduction and symptom control rather than disease modification. These pharmaceutical treatments are limited and can have unwanted side effects. The health and economical impact of OA has seen it become an international public health priority and has led to the active exploration and research of alternative regenerative and joint preservation therapies including mesenchymal stem cells.

Whilst both mechanical, genetic and other factors influence development of OA, the primary risk factor is age. Components of the cartilage extracellular matrix (ECM) including type II collagen and proteoglycans undergo age-related structural changes, leading to likely alteration in the biomechanical properties of the ECM. Advanced glycosylation end products also accumulate within cartilage, leading to increased cross-linking and altered biomechanical properties. These changes lead to a loss in the ability of cartilage to adapt to mechanical stress/load. Chondrocytes within the cartilage matrix also exhibit age related changes. It has been proposed that reactive oxygen species (free radicals) induced by mechanical or biological stressors may lead to cell senescence. Cell senescence is accompanied by reduced growth factor response and production, coupled with an observed upregulation of inflammatory cytokine expression. Evidently there are a host of enzymatic compounds that are involved in the disruption of the collagen matrix leading to the degradative process of OA.

Interestingly, evidence indicates that osteoarthritis is associated with a depleted local population of stromal mesenchymal stem cells (MSCs), and those that exist exhibit reduced proliferative and differentiation capacity. The depletion and functional alteration/down regulation of MSC populations with reduced differentiation capacity has also been postulated as a cause for progressive degenerative OA. Despite these findings, it has been noted that there exists MSCs with chondrogenic differentiation potential in patients with OA, irrespective of age or the etiology of disease.

MSCs, due to ease of harvest and isolation with minimal donor site morbidity, coupled with an ability to expand into chondrocytes, have meant that they have been actively explored in regards to tissue engineering and repair. Preclinical trials using techniques similar to autologous harvesting of cartilage from a non-weight bearing area, but substituting chondrocytes with MSCs, have shown positive results with formation of tissue with histological properties consistent with hyaline cartilage and a high type II collagen presence. Others have successfully transplanted isolated MSCs - seeded onto a type I collagen network - to an area of chondral defect, resulting in successful filling of the defect. Later biopsy at two years indicated hyaline like cartilage with type II collagen on histological evaluation.

Recognizing the limitation of biological scaffolds in the treatment of OA - where there exists more diffuse cartilage loss rather than an isolated cartilage lesion - other researchers have sought to assess the effect of intra-articular MSC injections. Preclinical trials have successfully indicated the benefit of MSC intra-articular injections on improvement in function, though results have been inconsistent on cartilage restoration. Some studies, whilst indicating significant pain and functional improvement, have not seen any observable difference in disease progression against controls, whilst others have successfully shown disease modification. Similarly to preclinical results, clinical trials using injectable MSC techniques have reproducibly shown pain and function improvements, though observation of disease modification has been less consistent. Most recently, Phase I and II trials using expanded adipose derived MSCs in the treatment of OA have shown MRI evidence of cartilage regrowth. Following a single intra-articular injection of 100 million MSCs, radiological (MRI) follow-up at 6 months showed increased cartilage volume and histological assessment confirmed hyaline-like cartilage regeneration with the presence of type II collagen.

Despite MSCs being commonly associated with regenerative medicine, and level IV evidence of chondral regrowth and disease modification, there is a paucity of well-controlled trials assessing structural outcome. The reproducible pain and functional improvement seen with MSC injectable therapies, raises the question of whether the biological mechanism of action may be a strong anti-inflammatory effect - including on neurogenic inflammation - rather than regeneration. Further, the observed disease modification in studies that use combination therapy suggests that the efficacy of MSC therapies may be influenced by additional agents including platelet concentrates and hyaluronic acid - though this creates a further layer of confusion regarding cause and effect. Nonetheless, MSC based cell therapies offer an exciting possibility in the treatment of OA and importantly show promise in disease modification, with potential inhibition of progression and recent evidence of reversal of this degenerative process.


The paper and publicity materials I'll point out today are one example of a range of recent investigations of blood-brain barrier dysfunction in Alzheimer's disease patients. The interior of the brain is its own strange domain, shut off from the rest of the body by the blood-brain barrier. Every system fails over the course of aging, however, and this barrier is no exception. There is a good amount of evidence linking increased leakage of the blood-brain barrier with the progression of neurodegenerative conditions such as Alzheimer's disease. Though, as in all such things, we must remember that aging is a global phenomenon, based on the accumulation of forms of cell and tissue damage that occur throughout the body, and thus correlations between many diverse aspects of aging can be found even when there are no direct links between them. Good research must include additional evidence beyond mere association.

What is the blood-brain barrier? The brain is laced with an intricate network of blood vessels large and small, pumping in oxygenated blood, nutrients, and an enormous range of proteins and other materials from the rest of the body. The blood-brain barrier is made up of cells that line every last millimeter of those blood vessels, each joined membrane to membrane with its neighbors in what are called tight junctions. These cells act as gatekeepers, allowing only a specific range of molecules to pass either to or from the brain tissue beyond the blood vessels. If the wrong materials leak or spill into the brain, the result is inflammation and damage - and all of the important neurodegenerative conditions are accelerated by higher levels of inflammation in brain tissues. Equally problematic is failure in the opposite direction, in which a faulty blood-brain barrier traps metabolic waste and other problem molecules in the brain rather than allowing their removal.

What to do about all of this? There is some evidence to suggest that exercise slows blood-brain barrier degeneration, but then exercise modestly slows aging across the board. Calorie restriction is much the same. Beyond these methods of slightly putting off the inevitable, one of the few plausible approaches to addressing blood-brain barrier failure is implementation of the SENS repair-based approaches to aging. Fix all of the fundamental cell and tissue damage known to cause aging, and see how things go from there. Accurately mapping the many, many intermediary steps of cause and consequence between initial damage and end result of blood-brain barrier failure is a massive project for the research community, far harder than fixing damage, even for this one small slice of aging - so why prioritize that path? The faster approach is to repair damage and observe results; if we are truly concerned about treating aging as a medical condition, alleviating suffering and rejuvenating the old rather than merely gathering data, then speed of action is a primary concern.

Leaky blood-brain barrier linked to Alzheimer's disease

Researchers using contrast-enhanced MRI have identified leakages in the blood-brain barrier (BBB) of people with early Alzheimer's disease (AD). The results suggest that increased BBB permeability may represent a key mechanism in the early stages of the disease. For the study, researchers used contrast-enhanced MRI to compare 16 early AD patients with 17 healthy age-matched controls. They measured BBB leakage rates and generated a map called a histogram to help determine the amount of the leaking brain tissue.

The BBB leakage rate was significantly higher in AD patients compared with controls and the leakage was distributed throughout the cerebrum - the largest part of the brain. AD patients had a significantly higher percentage of leaking brain tissue in the gray matter, including the cortex, the brain's outer layer. The researchers also found very subtle BBB impairment in the brain's white matter. Indeed, the researchers found a relationship between the extent of BBB impairment and decline in cognitive performance, suggesting that a compromised BBB is part of the early pathology of AD and might be part of a cascade of events eventually leading to cognitive decline and dementia. The connection between BBB impairment and AD pathology was strengthened by the fact that the addition of diabetes and other non-cerebral vascular diseases to the analysis model did not change the results.

Blood-Brain Barrier Leakage in Patients with Early Alzheimer Disease

For this pilot study, 16 patients with early AD and 17 healthy age-matched control subjects underwent dynamic contrast material-enhanced magnetic resonance (MR) imaging sequence with dual time resolution for 25 minutes. The Patlak graphical approach was used to quantify the BBB leakage rate and local blood plasma volume. Subsequent histogram analysis was used to determine the volume fraction of the leaking brain tissue. The BBB leakage rate was significantly higher in patients compared with that in control subjects in the total gray matter and cortex. Patients had a significantly higher volume fraction of the leaking brain tissue in the gray matter, normal-appearing white matter, deep gray matter, and cortex. When all subjects were considered, scores on the Mini-Mental State Examination decreased significantly with increasing leakage in the deep gray matter and cortex.

Not only did this show that the differences between patients with early AD and healthy control subjects were in the extent of the BBB leakage rather than the rate (ie, strength), but it also showed that the leakage was widespread rather than localized to a single tissue class. In addition, the BBB impairment did not fully originate from vascular abnormality, because adding diabetes and other noncerebral vascular diseases to the analysis model did not change the results. This suggested that the BBB impairment stemmed from the AD abnormality instead of from vascular comorbidities.

The leakage observed in this study can be explained as a breakdown of the BBB tight junctions. It has been shown in rodents that tight junction damage allows gadolinium leakage through the BBB. The regions with high BBB leakage were diffusely distributed throughout the brain, showing that BBB tight junctions were globally impaired. This could have allowed the passage of small and lipophilic molecules that could not cross a healthy BBB. The loss of tight junctions also changes cell polarity, which influences the expression of transporter complexes and thus indirectly affects active transport across the BBB. Therefore, both passive and active transport mechanisms may be impaired in patients with early AD, possibly disturbing homeostasis. We found that cognitive decline was associated with stronger BBB leakage, and both the patients with MCI and those with early AD showed increased BBB leakage. These observations suggest that BBB impairment may be a contributing factor in the early pathophysiology of AD. A possible mechanism is that loss of tight junctions impairs the filter function of the BBB, leading to a toxic accumulation of substances in the brain. This, combined with the altered active transport systems, might add up to a substantial effect on neuronal function that eventually leads to dementia.


To follow on from the post on reactive oxygen species in aging earlier today, I thought I'd direct your attention to a few more recent papers that approach this topic from various directions. To recap, it has long been known that the level of oxidative damage in cells increases with age, a state of affairs called oxidative stress, and that this is largely a product of changes in mitochondria, the power plants of the cell where more energetic chemistry takes place. What does this mean? Cells are intricate, dynamic, mostly fluid bundles of molecular machinery, and roving reactive molecules - such as reactive oxygen species (ROS) - cause harm by reacting with this machinery so as to prevent it from functioning correctly. When there are more such reactive molecules, there is a higher rate of ongoing damage, and cells must work harder to maintain correct functionality and behavior.

Oxidative stress in the general sense of the flux of cell damage versus cell repair features prominently in the past generation of theories of aging, but since those theories were first proposed, further investigation of the roles and relationships involving ROS has considerably complicated the picture. It isn't a straightforward case of more oxidative stress creating faster aging, with a clear set of changes driving degeneration at every step. The bulk of oxidative stress inside cells may be largely irrelevant in comparison to other facets and consequences of mitochondrial dysfunction, such as the generation of oxidized lipids that then enter the bloodstream.

The big picture is still incomplete, but it nonetheless seems that there is no straightforward relationship between aging, varying levels of ROS inside cells, and the many ways to measure oxidative stress. As it turns out ROS molecules are as much useful signals inside cells as they are a part of the damage and dysfunction of aging: methods of modestly extending life span in laboratory species can involve either higher or lower levels of ROS, depending on the details, and some long-lived species have all of the biochemical markers of high levels of oxidative stress but none of the expected dysfunction. Like all aspects of metabolism, complexity is the rule, and attempts to manipulate ROS-related mechanisms to obtain health benefits via the standard process of drug discovery and development will no doubt prove to be just as slow and expensive as other, similar approaches to shifting metabolism into a more advantageous state.

The bright side of reactive oxygen species: lifespan extension without cellular demise

Oxidative stress and the generation of reactive oxygen species (ROS) can lead to mitochondrial dysfunction, DNA damage, protein misfolding, programmed cell death with apoptosis and autophagy, and the promotion of aging-dependent processes. Mitochondria control the processing of redox energy that yields adenosine triphosphate (ATP). Ultimately, the generation of ROS occurs with the aerobic production of ATP. Although reduced levels of ROS may lead to tolerance against metabolic, mechanical, and oxidative stressors and the generation of brief periods of ROS during ischemia-reperfusion models may limit cellular injury, under most circumstances ROS and mitochondrial dysfunction can lead to apoptotic caspase activation and autophagy induction that can result in cellular demise. Yet, new work suggests that ROS generation may have a positive impact through respiratory complex I reverse electron transport that can extend lifespan. Such mechanisms may bring new insight into clinically relevant disorders that are linked to cellular senescence and aging of the body's system. Further investigation of the potential "bright side" of ROS and mitochondrial respiration is necessary to target specific pathways that can impact oxidative stress-ROS mechanisms to extend lifespan and eliminate disease onset.

Roles for ROS and hydrogen sulfide in the longevity response to germline loss in Caenorhabditis elegans

Signals from reproductive tissues and germ cells influence the lifespans of many organisms, including mammals. How germ cells, which give rise to the next generation, control the aging of the animal in which they reside is poorly understood. Counter-intuitively, we found that removing germ cells in Caenorhabditis elegans triggers the generation of two potentially toxic substances, reactive oxygen species (ROS) and hydrogen sulfide (H2S), in nonreproductive somatic tissues. These substances, in turn, induce protective responses that slow aging. A cytoskeletal protein, KRI-1, plays a key role in the generation of H2S and ROS. These kri-1-dependent redox species, in turn, promote life extension by activating SKN-1/Nrf2 and the mitochondrial unfolded-protein response, respectively. Both H2S and, remarkably, kri-1-dependent ROS are required for the life extension produced by low levels of the superoxide-generator paraquat and by a mutation that inhibits respiration. Together our findings link reproductive signaling to mitochondria and define an inducible, kri-1-dependent redox-signaling module that can be invoked in different contexts to extend life and counteract proteotoxicity.

Reactive oxygen species in sarcopenia: Should we focus on excess oxidative damage or defective redox signalling?

Physical frailty in the elderly is driven by loss of muscle mass and function and hence preventing this is the key to reduction in age-related physical frailty. Our current understanding of the key areas in which ROS contribute to age-related deficits in muscle is through increased oxidative damage to cell constituents and/or through induction of defective redox signalling. Recent data have argued against a primary role for ROS as a regulator of longevity, but studies have persistently indicated that aspects of the aging phenotype and age-related disorders may be mediated by ROS. There is increasing interest in the effects of defective redox signalling in aging and some studies now indicate that this process may be important in reducing the integrity of the aging neuromuscular system. Understanding how redox-signalling pathways are altered by aging and the causes of the defective redox homeostasis seen in aging muscle provides opportunities to identify targeted interventions with the potential to slow or prevent age-related neuromuscular decline with a consequent improvement in quality of life for older people.

Mitochondrial Metabolism in the Aging Heart

Altered mitochondrial metabolism is the underlying basis for the increased sensitivity in the aged heart to stress. The aged heart exhibits impaired metabolic flexibility, with a decreased capacity to oxidize fatty acids and enhanced dependence on glucose metabolism. Aging impairs mitochondrial oxidative phosphorylation, with a greater role played by the mitochondria located between the myofibrils, the interfibrillar mitochondria. With aging, there is a decrease in activity of complexes III and IV, which account for the decrease in respiration. Furthermore, aging decreases mitochondrial content among the myofibrils. The end result is that in the interfibrillar area, there is ≈50% decrease in mitochondrial function, affecting all substrates. The defective mitochondria persist in the aged heart, leading to enhanced oxidant production and oxidative injury and the activation of oxidant signaling for cell death. Aging defects in mitochondria represent new therapeutic targets, whether by manipulation of the mitochondrial proteome, modulation of electron transport, activation of biogenesis or mitophagy, or the regulation of mitochondrial fission and fusion. These mechanisms provide new ways to attenuate cardiac disease in elders by preemptive treatment of age-related defects, in contrast to the treatment of disease-induced dysfunction.


The staples of cancer treatment remain chemotherapy and radiotherapy, even today. Despite tremendous progress in the laboratory and in trials, the medical community has not yet passed the point at which immunotherapy and other targeted approaches take over the mainstream. Thus cancer treatment programs are still very much a balancing act between harming the cancer and harming the patient, while metastasis is still largely the beginning of the end, in which cancer slips out of reach of the dosage of poisons a patient can survive. Neither chemotherapy nor radiation therapies are treatments that anyone would voluntarily undergo if there were any other viable options on the table, as they are simply not selective enough. The whole point of the next generation of targeted therapies is to retain the ability to harm cancer while removing near all of the harm done to the patient. That can even be achieved with present day chemotherapy drugs, if they can be delivered in minuscule doses and only to cancerous cells. It is easy to kill cells; the hard part has always been to kill only the cells that you want killed.

Thus most cancer therapy today is the carefully calibrated application of damage. Toxins and radiation cause inflammation, make cells become senescent, and create range of other effects, some temporary, some lasting. We can say the same for a smoking habit, a terrible thing to maintain unless your goal is to cut short your life and health. A useful distinction to make here is between primary aging and secondary aging. Primary aging is what your body does to you even under the best of circumstances: cell and tissue damage that accumulates as a form of biological wear and tear, created as a result of the normal, healthy operation of metabolism. Secondary aging is additional damage heaped upon you by your choices and by the environment: the effects of infectious disease, obesity, a sedentary lifestyle, smoking, and, of course, chemotherapy or radiotherapy. The line between primary and secondary aging is fuzzy at best. Senescent cells accumulate to cause harm and age-related disease even in the bodies of individuals with the best and most fortunate of lives. Their presence is one of the root causes of aging. If chemotherapy piles on an additional lingering population of these cells, secreting signals that disrupt metabolism and degrade tissue function, then do we call that accelerated aging? This paper answers that question in the affirmative:

Cancer Treatment as an Accelerated Aging Process: Assessment, Biomarkers, and Interventions

Presently, there are 8 million cancer survivors age 65 or older in the United States, and this number is anticipated to continue to grow to 11 million by 2020. A key survivorship issue facing these older adults is the short- and long-term impact of cancer therapy on the aging process. It has been suggested that cancer and/or its treatment may contribute to an accelerated aging phenotype. The majority of these data come from the pediatric literature, but a smaller yet growing body of literature points toward similar findings in the geriatric population.

The aging process is unique to the individual, and chronological age is a poor descriptor of an older adult. For example, two individuals who are chronologically age 75 can have very different functional ages. A geriatric assessment identifies factors other than chronological age that can predict the risk of morbidity and mortality in older adults. These include functional status, cognition, comorbidity, psychological state, social support, and nutritional status. Geriatric assessment is the cornerstone for assessing function in patients with cancer prior to treatment. It can be helpful in predicting survival, treatment-related toxicity, and other outcomes. However, geriatric assessment can be time consuming, and many clinicians do not have the resources to perform a geriatric assessment in daily practice. Biomarkers of aging may help fill this gap. Potential biomarkers include chronic inflammatory markers, markers of cellular senescence, and sarcopenia.

Inflammatory markers have been extensively studied, and increased levels have been shown to correlate with frailty, functional decline, and survival. These markers now are receiving wide attention, as there is good evidence that chronically elevated levels may accelerate or exacerbate the aging process. These markers, which include interleukins, tumor necrosis factors, and others, have been studied extensively in frail patients in whom they independently correlate with other measures of physical function. Interleukin-6 (IL-6) has probably been the most extensively studied cytokine and has been shown to predict functional decline, including a diminution in the ability to perform activities of daily living, poor ambulation, and decreased mobility. There also appears to be a major relationship between inflammatory markers and cell senescence. Senescent cells are viable and capable of secreting proinflammatory markers that have led to the definition of a senescence-associated secretory phenotype. To date, however, none of these markers has assumed a major role in clinical care or further studies designed to see if any single marker or combination might have an independent role in the management of the older patient with cancer. These studies would test whether such markers could be independent predictors of treatment tolerance, including acute and chronic toxicities, functional loss, and cognitive decline.

There is little doubt that the treatment of cancer, especially radiation therapy and chemotherapy, greatly accelerates aging. A recent overview of survivors of childhood cancer showed that these individuals were at greatly increased risk for substantial comorbidity and premature death. Data from one of the large cohorts described in this review demonstrated the cumulative prevalence for a serious or life-threatening chronic condition of 81% by age 45; in addition, there was an extremely high incidence of second neoplasms that was directly related to the radiation dose. In another study of survivors of childhood cancer, the prevalence of prefrailty and frailty were 31.5 and 13.1% among women and 12.9 and 2.7% among men, respectively. This prevalence of frailty among young adult survivors of cancer with a mean age of 34 years was similar to that of adults age 65 or older.

p16ink4a has major promise as a biomarker of chemotherapy toxicity. p16ink4a expression increases approximately 10-fold between ages 20 and 80, and this dynamic range provides for a more robust marker as a predictor of molecular aging. In one study of women receiving adjuvant chemotherapy for early-stage breast cancer, p16ink4a expression measured in peripheral blood T cells increased by almost one log2 order of magnitude immediately after treatment and remained elevated 12 months after treatment. This change corresponds to almost a 15-year increase in chronologic age. In this study, the cytokines VEGFA and monocyte chemotactic protein-1 also significantly increased and remained elevated at 12 months, but telomere length was not affected. In a cross-sectional cohort of patients in the same study, prior chemotherapy exposure was independently associated with increased p16ink4a expression comparable to 10 years of chronologic aging.

"Don't get cancer" is great advice. It is a pity that it is so very hard to follow in practice. For my money the most important work in the cancer research community is that focused on building technology platforms that can be applied to either all or many cancers with comparatively little additional work. Victory in the sense of control over cancer will only come by crushing down the time and cost required to defeat each new variety of cancerous cell. The present morass of slow and painstaking progress exists because it has historically required an entire lengthy research initiative to be focused on each one of the thousands of noteworthy individual types of cancer, and that is still largely how business is conducted in this industry. This must change, and thankfully the signs of that change are beginning to emerge.

One of the most promising fields of early stage cancer research, still only undertaken by a few scientific groups, is focused on interfering in telomere lengthening. Telomeres shorten with each cell division, and thus all cancers must continually lengthen their telomeres in order to survive. This is the one useful universal commonality shared by all cancers. There are a limited set of mechanism by which this telomere lengthening can take place: either telomerase or one of the less well mapped alternative lengthening of telomeres (ALT) processes. If that short list can all be blocked in a tissue-selective manner - or even blocked globally for a while - then that will be the end of cancer as a serious threat.


Regenerative of tissue is a very complex affair in which all sorts of different cell types and systems participate in their own individual ways, collaborating in an intricate dance that results in reconstruction. The overall theme is the same in all tissues, but the details vary widely by tissue type. So in skin, for example, eccrine sweat glands, the primary type of sweat gland, serve as the anchor points from which new epithelium grows. The sweat glands are reservoirs of highly regenerative cells that spring into action when needed, and construct new structures outwards from the gland, meeting in the middle between glands. The research I'll point out today shows that these cell populations retain regenerative capacity even in older age, but the authors argue that age-related changes in the physical characteristics of skin act to sabotage regenerative efforts, making it harder to build cohesive cellular structures.

Physical characteristics derive from the extracellular matrix, a lattice of support constructed by the cells that occupy its spaces. The details of extracellular matrix molecular structure determine the properties of tissue for everything from skin to bone: flexibility, elasticity, stiffness, resilience, ability to bear load, and so forth. Anything that disrupts this structure and its maintenance will alter its properties, usually for the worse. One important form of age-related damage is cross-linking, in which forms of sugary metabolic byproducts bind with molecules of the extracellular matrix, linking and limiting them. Some types of cross-link are long-lived, and our biochemistry is unable to remove them. This is one of the processes responsible for loss of elasticity in skin and blood vessels. Then there are senescent cells that accumulate in tissues with age, producing inflammation and acting to remodel the surrounding extracellular matrix in uncoordinated, detrimental ways. Other aspects of aging also have their contributions to make to the declining quality of the extracellular matrix, some more direct, some less so.

What can be done about this? Periodically repair the damage. Design drugs that can break down the cross-links that our biochemistry cannot handle. Develop drugs and gene therapies that selectively kill senescent cells. Follow through to create the full SENS portfolio of envisaged rejuvenation treatments, each of which repairs one of the forms of damage that cause aging, including those that drive the aging of skin. Given a functional rejuvenation toolkit, all of our sweat glands could get back to working as they did in youth, provided with an extracellular matrix freed from the burden of molecular damage. All too little effort is directed to this goal, even in this day and age of revolutionary progress in biotechnology, and that is one of the great shames of our era.

The Healing Function of Sweat Glands Declines with Age

A group of scientists and dermatologists are now looking at the role sweat glands play in how aging skin recovers from wounds. It's a step to better learn about aging skin, in order to better treat - and slow - the process. Their research compared 18 elderly subjects' skin to 18 young adults' skin, to see how each group healed from skin lesions. The lesions were smaller than the diameter of a pencil eraser, performed under local anesthesia. The researchers had already determined eccrine sweat glands, which are located throughout the body, are important for wound closure. They are major contributors of new cells that replace the cells that were lost due to injury.

"Since we know elderly people tend to sweat less than young adults, we concentrated on this healing function of sweat glands." In young people, they discovered sweat glands contributed more cells to wound closure than in aged adults. The cells in aged skin weren't as cohesive, either. Fewer cells participating, spaced further apart, means a delay in wound closure and a thinner repaired epidermis in aged versus young skin. It wasn't that the sweat glands were less active in older people, rather, that the environment in the aging skin had been slowly degraded, making the skin structures less able to support the new cells that were generated. "Limiting skin damage during the aging process is likely to limit the negative impact of aging on wound repair. This study teaches us that poor wound healing and wrinkling and sagging that occur in aging skin share similar mechanisms."

Reduced cell cohesiveness of outgrowths from eccrine sweat glands delays wound closure in elderly skin

Human skin heals more slowly in aged vs. young adults, but the mechanism for this delay is unclear. In humans, eccrine sweat glands (ESGs) and hair follicles underlying wounds generate cohesive keratinocyte outgrowths that expand to form the new epidermis. Our results confirm that the outgrowth of cells from ESGs is a major feature of repair in young skin. Strikingly, in aged skin, although ESG density is unaltered, less than 50% of the ESGs generate epithelial outgrowths during repair (vs. 100% in young). Surprisingly, aging does not alter the wound-induced proliferation response in hair follicles or ESGs. Instead, there is an overall reduced cohesiveness of keratinocytes in aged skin. Reduced cell-cell cohesiveness was most obvious in ESG-derived outgrowths that, when present, were surrounded by unconnected cells in the scab overlaying aged wounds.

Failure to form cohesive ESG outgrowths may reflect impaired interactions of keratinocytes with the damaged extracellular matrix (ECM) in aged skin. Previous work from our group and others has characterized in detail the age-associated damage to the skin dermal ECM, which includes increased collagen fiber fragmentation, reduced ECM resistance, and decreased tissue mechanical force. Although the ECM is well known for its role in providing structural scaffolds for embedded cells, recent studies have highlighted the importance of the ECM as underlying substrate for collective cell migration. For instance, increasing ECM rigidity (Young's modulus) enhances cellular traction forces and cell-cell adhesion. Thus, it is likely that reduced rigidity of skin ECM, as it occurs with aging, would reduce cell-cell cohesiveness as we observed in vivo. Altogether, these observations suggest that damage to the ECM in aged skin may mediate reduced cell-cell cohesiveness and thereby reduce the efficiency of the re-epithelialization process in aged skin.



Evolution has left mammals with only a limited ability to regenerate heart tissue. Unlike very regenerative species such as salamanders or zebrafish, we lose most of our ability to heal the heart very early in life. Here, researchers suggest that this is keyed to reduced telomere length in heart cells, but in a way that is very different to the more familiar erosion of average telomere length that occurs over the course of aging. In this case that reduced length is a developmental process occurring in early childhood. If this work bears out, it actually sounds like a much more compelling argument for the use of telomerase therapies in medicine than those based on trying to address age-related telomere erosion, as that erosion is most likely only a marker of age-related damage, not a cause:

Researchers have discovered that the ends of heart muscle cell chromosomes rapidly erode after birth, limiting the cells' ability to proliferate and replace damaged heart tissue. Newborn babies can repair injured myocardium, but, in adults, heart attacks cause permanent damage, often leading to heart failure and death. Newborn mice can also regenerate damaged heart tissue. Their heart muscle cells, or cardiomyocytes, can proliferate and repair the heart in the first week after birth, but this regenerative capacity is lost as the mice grow older and the majority of their cardiomyocytes withdraw from the cell cycle.

Researchers wondered whether the cause of this cell cycle arrest might involve telomeres, repetitive DNA sequences that protect the ends of chromosomes. If telomeres grow too short - due, for example, to a loss of the telomere-extending telomerase enzyme - cells can mistake chromosome ends for segments of damaged DNA, leading to the activation of a checkpoint that arrests the cell cycle. The researchers therefore examined the length of telomeres in newborn mouse cardiomyocytes and found that the telomeres rapidly eroded in the first week after birth. This erosion coincided with a decrease in telomerase expression and was accompanied by the activation of the DNA damage response and a cell cycle inhibitor called p21.

Telomerase-deficient mice have shorter telomeres than wild-type animals, and, the researchers discovered, their cardiomyocytes already begin to stop proliferating one day after birth. When the researchers injured the hearts of one-day-old mice, telomerase-deficient cardiomyocytes failed to proliferate or regenerate the injured myocardium. In contrast, wild-type cardiomyocytes were able to proliferate and replace the damaged tissue. They also found that knocking out the cell cycle inhibitor p21 extended the regenerative capacity of cardiomyocytes, allowing one-week-old p21-deficient mice to repair damaged cardiac tissue much more effectively than week-old wild-type animals. Maintaining the length of cardiomyocyte telomeres might therefore boost the regenerative capacity of adult cells, improving the recovery of cardiac tissue following a heart attack. "We are now developing telomerase overexpression mouse models to see if we can extend the regenerative window."


In past years researchers have demonstrated in animal studies that reduced levels of klotho can shorten life span while increased levels modestly extend life span. The underlying mechanisms are complex and not fully understood. As is also the case for other longevity-related proteins, altering levels in circulation through gene therapy or other methods changes many aspects of cellular metabolism. Unraveling this complexity is a slow and expensive process. One small part of the bigger picture in this case is the relationship between klotho and fibroblast growth factor 23 (FGF23). The review paper below examines what is known on this topic:

Fibroblast growth factor-23 (FGF23) is a bone-derived hormone known to suppress phosphate reabsorption and vitamin D hormone production in the kidney. Klotho was originally discovered as an anti-aging factor, but the functional role of Klotho is still a controversial issue. Three major functions have been proposed, a hormonal function of soluble Klotho, an enzymatic function as glycosidase, and the function as an obligatory co-receptor for FGF23 signaling. The purpose of this review is to highlight the recent advances in the area of FGF23 and Klotho signaling in the kidney, in the parathyroid gland, in the cardiovascular system, in bone, and in the central nervous system.

Recent advances in the field of FGF23 and Klotho biology have revealed major new functions of FGF23 and Klotho signaling in the kidney, in the heart, in bone, in blood vessels, and in the parathyroid gland. It is now clear that FGF23 is far more than only a phosphaturic bone-derived hormone. Rather, FGF23 has emerged as a pleiotropic endocrine and auto-/paracrine factor not only involved in phosphate homeostasis, but also in calcium and sodium metabolism, in bone mineralization as well as in the development of cardiac hypertrophy. These novel findings have linked phosphate with volume homeostasis, and may have major pathophysiological implications for chronic kidney disease, cardiovascular diseases, and disorders of bone mineralization.


This popular science article takes a look at efforts to develop nanoparticles capable of reducing the size of plaques in blood vessels produced by the processes of atherosclerosis. These plaques narrow and deform blood vessels, ultimately breaking apart to cause blockages and ruptures of blood vessels that are often fatal. Atherosclerosis is caused at root by damaged lipids that enter the circulation and lodge in blood vessel tissue. This is followed by an unfortunate set of self-reinforcing signals sent by cells in the blood vessel wall and then by immune cells that turn up to try to deal with the problem. When immune cells become overwhelmed by ingesting damaged lipids, their destruction produces yet more debris, and plaques consisting of lipids and dead cells grow. Chronic inflammation can also accelerate this process, and aging is characterized by rising levels of inflammation. Treatments like the one profiled in this article do not treat the root causes of the problem, but regardless of success in addressing those root causes, large plaques will still need to be removed in people old enough to have developed them:

Careening through the bloodstream, a single nanoparticle is dwarfed by red blood cells whizzing by that are 100 times larger. But when specially designed nanoparticles bump into an atherosclerotic plaque - a fatty clog narrowing a blood vessel - the tiny particles can play an outsized role. They can cling to the plaque and begin to break it down, clearing the path for those big blood cells to flow more easily and calming the angry inflammation in the vicinity. By finding and busting apart plaques in the arteries, nanoparticles may offer a new, non-surgical way to reduce a patient's risk for heart attack and stroke. Some nanoparticles home in on the plaques by binding to immune cells in the area, some do so by mimicking natural cholesterol molecules and others search for collagen exposed in damaged vessel walls. Once at the location of a plaque, either the nanoparticles themselves or a piggybacked drug can do the cleanup work. Today, cardiovascular nanoparticles are still far from pharmacy shelves. Most have not reached safety testing in patients. But in mice, rats and pigs, nanodrugs have slowed the growth of the plaques that build up on vessel walls, and in some cases have been able to shrink or clear them. "I think the effect we can have with these nanoparticles on cardiovascular disease is even more pronounced and direct than what we've seen in cancer."

Many of the immune cells involved in atherosclerosis are macrophages, white blood cells that gulp pathogens, dead cells or debris in the body. At the site of a plaque, macrophages become swollen with fats and transform into what are called "foam cells" because of their foamy appearance. As they digest fats, foam cells send out chemical signals to recruit more inflammation-causing cells and molecules to the area. Because they're so intimately involved in the formation of plaques, macrophages and foam cells are a prime target for nanoparticles. One research group has designed nanoparticles that bind to molecules on the surface of macrophages, preventing them from gobbling fats and becoming foam cells. The researchers made the nanoparticles specifically target a subtype of macrophage that's involved in atherosclerosis, not the macrophages that might respond to other injuries in the body. When nanoparticles were injected into mice with narrowed arteries, the blockages decreased by 37 percent.

Another research group has designed HDL-mimicking nanoparticles. The particles deliver statins that make a beeline for macrophages and plaques, letting them administer the drug at lower-than-usual doses. The researchers were inspired by earlier studies that showed how extremely high doses of statins, given to mice, could lower LDL levels while also packing anti-inflammatory properties. Of course, in humans, such high doses would probably cause liver or kidney damage. The solution: tack the statins to a nanoparticle to send them, missile-like, to the plaques. That way, a low dose of the drug could achieve the high concentration needed at the site of the atherosclerosis. The group reported that plaque-filled arteries in mice given the nanoparticle were 16 percent more open than arteries in mice with no treatment, and 12 percent more open than in mice given a systemic statin.

The inflamed vessel wall around an atherosclerotic plaque goes through several changes in addition to the accumulation of belligerent immune molecules. As vessel walls are stretched and inflamed, the structural protein collagen, meant to keep the vessels taut and tubular, becomes exposed the way the threads of a tire begin to appear as it wears down. Scientists are using the exposed collagen to their advantage. Their nanoparticle combines a collagen-binding protein with nitric oxide, a molecule that stimulates the growth of new cells at wounds. To maximize the surface area of the drug that contacts the vessel wall, the team arranged the molecules in a line, forming a nanofiber, rather than a sphere. As the fiber is swept through the bloodstream, it binds to exposed collagen, anchoring the nitric oxide in place to spur healing of the artery. The researchers added fluorescent tags to the nanofibers and showed that the fibers congregated at injured spots on mouse arteries within an hour of injection. The tagged particles remained there for three days and the treated vessels ended up 41 percent more open.


Valter Longo's research group has for the past few years been gathering data in clinical trials on the effects of a short-term low-calorie diet that achieves enough of the benefits of fasting to be useful. In essence the researchers have been in search of the 80/20 point in reduced caloric intake at which most of the triggers of outright fasting are hit, and thus the resulting changes in metabolic processes look fairly similar to those produced by fasting for the same period of time. The result, a fasting-mimicking diet, has been deployed as a cancer adjuvant therapy, but the researchers are interested in finding other uses as well. Here, results are presented for a study of its effects on multiple sclerosis in animal models of the disease and human patients.

As much as the science and the new data, the progress achieved by this group has been a matter of attracting new funding to calorie restriction and intermittent fasting research. Formulating the fasting mimicking approach as a medical diet that companies can package, sell, and bill for within the current dysfunctional medical system - even though anyone can easily replicate it on their own - has proven to be a very viable way to gain research funding from sources that have previously had little interest in this field.

Evidence is mounting that a diet mimicking the effects of fasting has health benefits beyond weight loss, with a new study indicating that it may reduce symptoms of multiple sclerosis. Scientists discovered that the diet triggers a death-and-life process for cells that appears critical for the body's repair. "During the fasting-mimicking diet, cortisone is produced and that initiates a killing of autoimmune cells. This process also leads to the production of new healthy cells." These latest findings follow studies that showed cycles of a similar but shorter fasting-mimicking diet, when paired with drug treatments for cancer, protect normal cells while weakening cancerous ones. The lab found that the diet can cut visceral belly fat and reduce markers of aging and diseases in mice and humans. "We started thinking: If it kills a lot of immune cells and turns on the stem cells, is it possible that maybe it will kill the bad ones and then generate new good ones? That's why we started this study."

For the first part of the study, researchers put a group of mice with autoimmune disease on a fasting-mimicking diet for three days, every seven days for three cycles, with a control group on a standard diet for comparison. Results showed that the fasting-mimicking diet reduced disease symptoms in all the mice and "caused complete recovery for 20 percent of the animals." Testing the mice, the researchers found reductions in symptoms attributed to health improvements such as increased levels of the steroid hormone corticosterone, which is released by the adrenal glands to control metabolism. They also saw a reduction in the inflammation-causing cytokines - proteins that order other cells to repair sites of trauma, infection or other pain. They also saw improvements in the white blood "T cells," responsible for immunity. Finally, the researchers found that the fasting-mimicking diet promotes regeneration of the myelin - the sheath of proteins and fats that insulate nerve fibers in the spine and brain - that was damaged by the autoimmunity.

The researchers also checked the safety and potential efficacy of the diet on people who have multiple sclerosis through a pilot trial with 60 participants with the disease. Eighteen patients were placed on the fasting-mimicking diet for a seven day cycle and then placed on a Mediterranean diet for six months. Also for six months, 12 participants were on a controlled diet, and 18 others were on a ketogenic diet (a high-fat diet). Those who received a fasting-mimicking diet cycle followed by the Mediterranean diet and those on a ketogenic diet reported improvements in their quality of life and improvements in health, including physical and mental health. The researchers noted that the study is limited because it did not test whether the Mediterranean diet alone would cause improvements, nor did it involve a functional MRI or immune function analysis.


Researchers here theorize on the role of bacteria in stimulating immune function and other aspects of our biology in a positive way, with a focus on the FOXN1 protein. Increased FOXN1 in old mice has been demonstrated to restore the thymus to more youthful activity, and thus improve immune function. The thymus is where some classes of immune cell mature, and because it atrophies early in adulthood, the flow of new immune cells is much reduced over most of the life span. This low rate of production is a contributing factor to the age-related limits and decline of the immune system. Any method that rejuvenates the thymus, or that otherwise produces a large supply of new immune cells, will do a lot for immune function in old age. It isn't a fix for all of the issues by any means, but it is a fix for one of them, and in this new age of cheap and effective gene therapy, boosting the levels of individual proteins isn't an unreasonable thing to aim for in the years ahead.

The popularity of hand sanitizer and antibiotics shows how we feel about bacteria: an enemy that's bad for our health. Emerging data, however, suggest just the opposite - that exposures to certain kinds of bacteria are beneficial for a long and healthy life. Specifically, mice consuming probiotic L. reuteri were shown to have larger skeletal muscles than untreated age-matched controls. A surprising additional finding was increased thymus gland size only in mice consuming bacteria in their drinking water. The thymus was not only larger, but also had increased expression of Forkhead Box N1 (FoxN1), a feature involved in systemic programming of immune system lymphocytes.

Bacterial stimulation of FoxN1 and increased thymus gland size has enormous implications for host good health. Indeed, FoxN1 protein has been touted as a "Fountain of Youth". During childhood, a proficient thymus gland supplies adaptive immune cells that help fight pathogenic infections and discern self versus non-self, to lower risk of autoimmune diseases. With increasing age, the thymus gland naturally shrinks leading to immune dysregulation with higher risk for infections and cancer in elderly subjects. Other studies have shown that mouse models treated exogenously with FoxN1 had features of sustained youth. Interestingly, animals lacking FoxN1 failed to develop larger muscles after microbial therapy, implicating the immune system in muscle-boosting effects.

The precise mechanism by which bacteria stimulate FoxN1 expression in the thymus gland remains unknown but likely involves the wnt signaling pathway. Microbes have been shown by our own lab and by others to prime the immune system for sustained good health. At the same time, the thymus gland and muscle growth may also be stimulated through bacteria-triggered upregulation of central nervous system (CNS) hormones, for example growth hormone and oxytocin. Perhaps exposures to bacteria can be good for us, after all. Can we formulate a bacteria cocktail that prevents muscle loss with aging and imparts a long, healthy, and meaningful life? Additional research is needed to explore the vast and far-reaching potential of microbes for a long and healthy life.


Here, researchers use genetic engineering try to pin down specific sources of oxidizing molecules within a cell and identify their different effects on health and longevity. Cells are liquid bags of chemical machinery, and the presence of too many reactive oxygen species (ROS) - also known as free radicals - can produce a level of damage to that machinery that significantly impacts cell function, or even kills cells. This is known as oxidative stress, and levels of oxidative stress are seen to rise alongside the other manifestations of degenerative aging. However, ROS molecules are also used as signals: produced by mitochondria and triggering increased cell maintenance, among other activities. They are critical in the beneficial response to exercise, for example. Many methods of modestly extending life span in laboratory species involve reductions in levels of ROS, and many others involve increases - either can under the right circumstances extend healthy life by reducing net levels of cell damage or triggering other mechanisms relevant to health. A cell is a complex, reactive system and few aspects of cell state have straightforward relationships with one another. Oxidative stress features prominently in many theories of aging, but many of these theories are older and too simplified to be useful given the present state of knowledge and explorations of oxidative stress and ROS signaling.

Historically, mitochondrial ROS (mtROS) production and oxidative damage have been associated with aging and age-related diseases such as Parkinson's disease. In fact, the age-related increase in ROS has been viewed as a cause of the aging process while mitochondrial dysfunction is considered a hallmark of aging, as a consequence of ROS accumulation. However, pioneering work in Caenorhabditis elegans has shown that mutations in genes encoding subunits of the electron transport chain (ETC) or genes required for biosynthesis of ubiquinone extend lifespan despite reducing mitochondrial function. The lifespan extension conferred by many of these alterations is ROS dependent, as reduction of ROS abolishes this effect. Various studies have shown that ROS act as secondary messengers in many cellular pathways, including those which protect against or repair damage. ROS-dependent activation of these protective pathways may explain their positive effect on lifespan. The confusion over the apparent dual nature of ROS may, in part, be due to a lack of resolution as without focused genetic or biochemical models it is impossible to determine the site from which ROS originate.

A promising path to resolving ROS production in vivo is the use of alternative respiratory enzymes, absent from mammals and flies, to modulate ROS generation at specific sites of the ETC. The alternative oxidase (AOX) of Ciona intestinalis is a cyanide-resistant terminal oxidase able to reduce oxygen to water with electrons from reduced ubiquinone (CoQ), thus bypassing complex III and complex IV. NDI1 is a rotenone-insensitive alternative NADH dehydrogenase found in plants and fungi, which is present on the matrix-face of the mitochondrial inner membrane where it is able to oxidize NADH and reduce ubiquinone, effectively bypassing complex I. Our group and others have demonstrated that allotopic expression of NDI1 in Drosophila melanogaster can extend lifespan under a variety of conditions and rescue developmental lethality in flies with an RNAi-mediated decrease in complex I levels.

To determine the role of increased ROS production in regulating longevity, we utilized allotopic expression of NDI1 and AOX, along with Drosophila genetic tools to regulate ROS production from specific sites in the ETC. We report that ROS increase with age as mitochondrial function deteriorates. However, we also demonstrate that increasing ROS production specifically through respiratory complex I reverse electron transport extends Drosophila lifespan. We show that NDI1 over-reduces the CoQ pool and increases ROS via reverse electron transport (RET) through complex I. Importantly, restoration of CoQ redox state via NDI1 expression rescued mitochondrial function and longevity in two distinct models of mitochondrial dysfunction. If the mechanism we describe here is conserved in mammals, manipulation of the redox state of CoQ may be a strategy for the extension of both mean and maximum lifespan and the road to new therapeutic interventions for aging and age-related diseases.


Researchers investigating telomeres, telomerase, and aging are now trying to isolate effects of telomere length from effects of telomerase by employing a novel method of breeding mice with very long telomeres. Telomeres are repeated DNA sequences at the ends of chromosomes that form a part of the limiting mechanism for cell division. Telomere length falls with each cell division, cells self-destruct or become senescent when telomere length is short, and stem cells employ telomerase to lengthen their telomeres to retain their ability to generate new daughter cells with long telomeres. Average telomere length in tissues then derives from some combination of cell division rates and cell replacement rates, and tends to fall over the course of aging. Work on lengthening telomeres in mice over the past decade has focused on the use of telomerase, such as via gene therapy. This has been shown to extend life and improve health, an outcome likely to derive from increased stem cell activity.

But is the telomere length or is it the telomerase? Telomerase lengthens telomeres, yes, but that isn't its only activity. Like all proteins, it plays a role in many mechanisms, not all of which are fully mapped at this point. A sizable fraction of the research community see reduction in average telomere length as an outcome of the state of age and damage - a marker of aging, and not a cause of aging. In this context, finding a way to extend telomere length without the use of telomerase is a good choice for further exploration of the mechanisms, and that is the achievement made by the research team in this case. The results of this study, demonstrating a slowing of some measures of aging purely based on longer telomeres, present a challenge to the view of telomere length as a marker only, though we can still argue over whether it is a primary or secondary mechanism of aging, especially when measured in immune cells. Possible mechanisms of enhanced health that could derive from telomere length only might include lower levels of cellular senescence, for example, and it would be interesting to see that measured.

Researchers have succeeded in creating mice in the laboratory with hyper-long telomeres and with reduced molecular ageing, avoiding the use of what to date has been the standard method: genetic manipulation. This new technique based on epigenetic changes avoids the manipulation of genes in order to delay molecular ageing. In 2009 researchers described that the in vitro culture of induced pluripotent stem cells caused the progressive lengthening of telomeres, to the point of generating what the authors called "hyper-long telomeres". Sometime later, in 2011, it was found that this phenomenon also occurs spontaneously in embryonic stem cells when cultured in vitro. The in vitro expansion of the embryonic stem cells results in the elongation of the telomeres up to twice their normal length, and without alterations in the telomerase gene. However, would these cells be capable of developing into a mouse with telomeres that are much longer than normal and that would age more slowly? Researchers now prove that this is the case.

The cells with hyper-long telomeres in these mice appear to be perfectly functional. When the tissues were analysed at various moments (0, 1, 6 and 12 months of life), these cells maintained the additional length scale (they shortened over time but at a normal rhythm), accumulated less DNA damage and had a greater capacity to repair any damage. In addition, the animals presented a lower tumour incidence than normal mice. These results show that pluripotent stem cells that carry hyper-long telomeres can give rise to organisms with telomeres that remain young at the molecular level for longer. According to the authors, this "proof of concept means that it is possible to generate adult tissue with longer telomeres in the absence of genetic modifications". The next step that the researchers are already working on will be to "generate a new species of mice in which the telomeres of all the cells are twice as long as those in normal mice. Then, we will be able to address some of the important questions that remain unanswered: would a mouse species with telomeres that are double in length live longer? Is this the mechanism that is used by nature to determine different longevities in genetically similar species? Would this new species present a higher or lower incidence of cancer?"


An approach using nanoparticles to deliver RNA to immune cells, so as to kick off an immune response targeted to a specific cancer, has been in the news of late. Immunotherapies of a wide variety of types will form the basis for the coming generation of cancer therapies, the replacements for the present staples of chemotherapy and radiotherapy, but there is far too much work taking place to comment on every single project. It is a matter of accident rather than merit as to which research results receive greater or lesser attention from the public and the media. With the immune system being as complicated as it is, there are a lot of different ways in which to manipulate its activities, and most are in principle capable of producing viable therapies. Competition in this marketplace is as much to find a reliably, cost-effective way to address many cancers with the same technology platform as it is to find treatments that work.

Researchers have published a description of the first example worldwide of a clinically relevant and systemic mRNA cancer immunotherapy. They outline a novel approach to target a nanoparticle mRNA vaccine (RNA-LPX) body-wide to dendritic cells in the spleen, lymph nodes and bone marrow, where a highly potent, dual-mechanism immune response mimicking a natural antiviral immune response is rapidly elicited. The dual mechanism involves both adaptive (T-cell-mediated) and innate (type-I interferon (IFN)-mediated) immune responses, with the IFN response being essential for full anti-tumor effects of the vaccines. "Our study introduces a novel class of extraordinarily potent cancer vaccines that enables efficient redirection of the immune system against a wide range of tumor antigens. This is a major step towards our aim to make truly personalized cancer immunotherapies available and applicable to all cancer types."

The researchers further provide mode of action and efficacy data for this novel vaccine class in several preclinical tumor models and reports early data from a phase I dose-escalation, safety and tolerability trial (NCT02410733) of an intravenous RNA-LPX vaccine in melanoma patients. Crucially, in these patients, very low initial doses, lower than those used in preclinical studies, very rapidly elicited such a strong CD4+ and CD8+ T cell response that ex vivo culture was not required for detection. To date this vaccine has been very well tolerated and no severe toxicities have been observed. The phase I melanoma study continues to recruit patients and researchers plan to execute additional RNA-LPX vaccine studies for different cancer types.


A small study of stem cell transplants into the brain has demonstrated striking benefits in stroke patients when administered long after the stroke itself, past the point at which any further natural recovery is expected:

Injecting modified, human, adult stem cells directly into the brains of chronic stroke patients proved not only safe but effective in restoring motor function, according to the findings of a small clinical trial. The patients, all of whom had suffered their first and only stroke between six months and three years before receiving the injections, remained conscious under light anesthesia throughout the procedure, which involved drilling a small hole through their skulls; the next day they all went home. Although more than three-quarters of them suffered from transient headaches afterward - probably due to the surgical procedure and the physical constraints employed to ensure its precision - there were no side effects attributable to the stem cells themselves, and no life-threatening adverse effects linked to the procedure used to administer them.

"This was just a single trial, and a small one. It was designed primarily to test the procedure's safety. But patients improved by several standard measures, and their improvement was not only statistically significant, but clinically meaningful. Their ability to move around has recovered visibly. That's unprecedented. At six months out from a stroke, you don't expect to see any further recovery." Although approved therapies for ischemic stroke exist, to be effective they must be applied within a few hours of the event - a time frame that often is exceeded by the amount of time it takes for a stroke patient to arrive at a treatment center. Consequently, only a small fraction of patients benefit from treatment during the stroke's acute phase. The great majority of survivors end up with enduring disabilities. Some lost functionality often returns, but it's typically limited.

For the trial, the investigators screened 379 patients and selected 18, whose average age was 61. Into these patients' brains the neurosurgeons injected so-called SB623 cells - mesenchymal stem cells derived from the bone marrow of two donors and then modified to beneficially alter the cells' ability to restore neurologic function. Afterward, patients were monitored via blood tests, clinical evaluations and brain imaging. Interestingly, the implanted stem cells themselves do not appear to survive very long in the brain. Preclinical studies have shown that these cells begin to disappear about one month after the procedure and are gone by two months. Yet, patients showed significant recovery by a number of measures within a month's time, and they continued improving for several months afterward, sustaining these improvements at six and 12 months after surgery. Substantial improvements were seen in patients' scores on several widely accepted metrics of stroke recovery. Perhaps most notably, there was an overall 11.4-point improvement on the motor-function component of the Fugl-Meyer test, which specifically gauges patients' movement deficits. "This wasn't just, 'They couldn't move their thumb, and now they can.' Patients who were in wheelchairs are walking now."


Fibrosis taken as a whole and in its surrounding context is more complicated than simply a matter of the wrong cells growing in the wrong place, but that is an important portion of it. The condition involves excess connective tissue forming in organs, a type of scarring process, and this degrades organ function. It is a notable component of both chronic liver and kidney disease, for example. Here, researchers demonstrate cellular reprogramming via gene therapy in mice that turns some of the connective tissue cell lineages into liver cell lineages, thus reducing the progression of fibrosis and restoring some of the lost liver cells:

Liver fibrosis, a form of scarring, develops in chronic liver diseases when hepatocyte regeneration cannot compensate for hepatocyte death. Initially, collage produced by myofibroblasts (MFs) functions to maintain the integrity of the liver, but excessive collagen accumulation suppresses residual hepatocyte function, leading to liver failure.

As a strategy to generate new hepatocytes and limit collagen deposition in the chronically injured liver, we developed in vivo reprogramming of MFs into hepatocytes using adeno-associated virus (AAV) vectors expressing hepatic transcription factors. We first identified the AAV6 capsid as effective in transducing MFs in a mouse model of liver fibrosis. We then showed in lineage-tracing mice that AAV6 vector-mediated in vivo hepatic reprogramming of MFs generates hepatocytes that replicate function and proliferation of primary hepatocytes, and reduces liver fibrosis. Because AAV vectors are already used for liver-directed human gene therapy, our strategy has potential for clinical translation into a therapy for liver fibrosis.

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