A good amount of evidence has been assembled by the scientific community to demonstrate that the innate immune cells called macrophages play a central role in tissue regeneration. Regeneration is an intricate dance of signaling between numerous cell types and cell states: stem cells, somatic cells, immune cells, and others. Macrophages supply necessary signals that help to guide regenerative processes. They are also responsible for destroying the temporary population of senescent cells that arises in wounds, cells that also deliver signals that promote regenerative activity. Senescent cells are useful in the short term, but if they linger they become disruptive and harmful.

One of the lines of evidence for the importance of macrophages in healing involves comparisons with species capable of highly proficient regeneration. In salamanders, regeneration of organs is dependent on the presence of macrophage signaling. Similarly, African spiny mice exhibit an unusually comprehensive regenerative capacity for mammals, and here again that is due to their macrophages.

Much of the investigative work on macrophages and regeneration has focused on muscle tissue, and the materials noted here today continue that theme. Researchers have been able to engineer small sections of functional muscle tissue for a number of years, with the inability to reliably produce capillary networks being the primary roadblock to the creation of large muscle sections for transplantation. Blood and nutrients can only perfuse through a few millimeters of solid tissue. These small organoids may be functional when it comes to the core capabilities of muscle tissue, but they are lacking when it comes to regenerative capacity. One logical approach to fixing this problem is to incorporate macrophages into the mix of cells, and judging from the results here, this works fairly well once the initial hurdles are overcome.

Macrophages enable regeneration of lab-grown adult muscle tissue

In 2014, researchers debuted the world's first self-healing, lab-grown skeletal muscle. The milestone was achieved by taking samples of muscle from rats just two days old, removing the cells, and "planting" them into a lab-made environment perfectly tailored to help them grow. For potential applications with human cells, muscle samples would be mostly taken from adult donors rather than newborns. There's just one problem - lab-made adult muscle tissues do not have the same regenerative potential as newborn tissue. "I spent a year exploring methods to engineer muscle tissues from adult rat samples that would self-heal after injury. Adding various drugs and growth factors known to help muscle repair had little effect, so I started to consider adding a supporting cell population that could react to injury and stimulate muscle regeneration. That's how I came up with macrophages, immune cells required for muscle's ability to self-repair in our bodies."

After a muscle injury, one class of macrophages shows up on the scene to clear the wreckage left behind, increase inflammation and stimulate other parts of the immune system. One of the cells they recruit is a second kind of macrophage, dubbed M2, that decreases inflammation and encourages tissue repair. While these anti-inflammatory macrophages had been used in muscle-healing therapies before, they had never been integrated into a platform aimed at growing complex muscle tissues outside of the body. "When we damaged the adult-derived engineered muscle with a toxin, we saw no functional recovery and muscle fibers would not build back. But after we added the macrophages in the muscle, we had a wow moment. The muscle grew back over 15 days and contracted almost like it did before injury. It was really remarkable."

The discovery may lead to a new line of research for potential regenerative therapies. According to a popular theory, fetal and newborn tissues are much better at healing than adult tissues at least in part because of an initial supply of tissue-resident macrophages that are similar to M2 macrophages. As individuals age, this original macrophage supply is replaced by less regenerative and more inflammatory macrophages coming from bone marrow and blood. "We believe that the macrophages in our engineered muscle system may behave more like the muscle-resident macrophages people are born with. We are currently working to understand if this is indeed the case. One could then envision 'training' macrophages to be better healers in a system like ours or augmenting them by genetic modifications and then implanting them into damaged sites in patients."

Incorporation of macrophages into engineered skeletal muscle enables enhanced muscle regeneration

Adult skeletal muscle has a robust capacity for self-repair, owing to synergies between muscle satellite cells and the immune system. In vitro models of muscle self-repair would facilitate the basic understanding of muscle regeneration and the screening of therapies for muscle disease. Here, we show that the incorporation of macrophages into muscle tissues engineered from adult-rat myogenic cells enables near-complete structural and functional repair after cardiotoxic injury in vitro.

First, we show that-in contrast with injured neonatal-derived engineered muscle-adult-derived engineered muscle fails to properly self-repair after injury, even when treated with pro-regenerative cytokines. We then show that rat bone-marrow-derived macrophages or human blood-derived macrophages resident within the in vitro engineered tissues stimulate muscle satellite cell-mediated myogenesis while significantly limiting myofibre apoptosis and degeneration. Moreover, bone-marrow-derived macrophages within engineered tissues implanted in a mouse model augmented blood vessel ingrowth, cell survival, muscle regeneration, and contractile function.

Idiopathic pulmonary fibrosis (IPF) appears to be significantly driven by the presence of senescent cells in the lungs. Other forms of fibrosis in other organs have been similarly linked to senescent cells. Increased cellular senescence is a feature of aging, and indeed is one of the root causes of aging. These cells secrete a potent mix of signals that induce inflammation, damage tissue structures, and change the behavior of nearby cells for the worse. In this context the results presented here are intriguing; the authors of this open access paper find that IPF patients have more senescent bone marrow stem cells.

There are a few ways to think about this. The first is that aging is a global phenomenon of accumulating molecular damage throughout the body, and people with enough damage to be predisposed to clinical levels of lung fibrosis are going to exhibit more pronounced measures of aging everywhere else as well. The second is that stem cells are negatively affected by high levels of inflammation, inflammatory signaling can spread widely by following the circulatory system, and the inflammatory conditions of IPF in lung tissues may thus be harming stem cell populations throughout the body. Lastly, one could argue causation in the other direction, as the researchers do here, suggesting that senescence of stem cells in bone marrow is a contributing factor to the development of IPF.

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease characterized by a progressive and irreversible loss of lung function though accumulation of scar tissue. Aging is considered the main risk factor for IPF. Along with others, we have demonstrated that there is an increase in markers of cell senescence in lung fibroblasts from IPF patients. Additionally, we have shown that, in animal models of lung injury, aged bone marrow-derived mesenchymal stem cells (B-MSCs) have decreased protective activity. This is in contrast to what we had previously described in young animal models of pulmonary fibrosis, where infusion of B-MSCs isolated from normal young donors in the initial stages of the injury results in a decrease in collagen deposition in the lung.

Therefore, we aimed to determine the differences in the biological and functional characteristics of B-MSCs from healthy individuals and IPF patients within the same age range. Characterization of IPF B-MSCs shows an increase in cell senescence linked to an upsurge of senescence-associated secretory phenotypes (SASPs) promoting a proinflammatory milieu and increasing deposition of components from the extracellular matrix. Our data suggest that extrapulmonary alterations in B-MSCs from IPF patients might contribute to the pathogenesis of the disease.

The consequences of having senescent B-MSCs are not completely understood, but the decrease in their ability to respond to normal activation and the risk of having a negative impact on the local niche by inducing inflammation and senescence in the neighboring cells suggests a new link between B-MSC and the onset of the disease.

Link: https://doi.org/10.1186/s13287-018-0970-6

Hypertension, raised blood pressure, is an important mediating mechanism in aging. It is caused by forms of low-level biochemical damage in and around the cells of blood vessel walls, and produces structural damage to organs and the cardiovascular system, leading to dysfunction and death. Hypertension is sufficiently harmful in and of itself that present methods of reducing blood pressure can reduce risk of mortality and clinical age-related disease, even given significant side-effects, and even given that none of these methods address the root causes of hypertension. They override reactions to damage rather than repairing damage. Repair of that damage, once implemented, should prove far more effective.

One of the ways in which hypertension damages organs is through an increased pace of rupture in capillaries and other forms of small-scale structural damage. This is particularly important in the brain, as it has only a very limited capacity to heal injuries of this nature. Cognitive decline driven by hypertension is in part a progression of tiny, unnoticed strokes, each destroying the function of a minuscule portion of the brain. Over time that adds up, and thus we might expect to observe correlations between hypertension and dementia. Nothing is simple in human data, of course, as even straightforward relationships can be challenging to extract from the very noisy data.

Hypertension is a highly prevalent condition, occurring in one-third of the world's adults and in two-thirds of adults over 65 years of age. Both hypertension and dementia are age-related comorbidities which may induce considerable disabilities. Some epidemiological studies showed that hypertension is an important risk factor of dementia, which was evident from the positive relationship between blood pressure at midlife and the subsequently higher risk of cognitive impairment or dementia late in life; however, some other studies provided contradictory evidence that low blood pressure was a risk factor for dementia and cognitive decline.

We, therefore, intend to explore the association between blood pressure and cognition. Data were drawn from 3,327 participants at the baseline of Shanghai Aging Study. History of hypertension was inquired and confirmed from participants' medical records. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured in the early morning. Participants were diagnosed with "cognitive normal," "mild cognitive impairment (MCI)," or "dementia" by neurologists. Multivariate logistic regression was used to evaluate the association between history of hypertension, duration of hypertension, SBP, DBP, or classification of blood pressure and cognitive function.

Our study indicated that history of hypertension, duration of hypertension, and high blood pressure were positively associated with dementia. A significantly higher proportion of hypertension [76.5%] was found in participants with dementia than in those with MCI [59.3%] and cognitive normal [51.1%]. Participants with dementia had significantly higher SBP [157.6 mmHg] than those with MCI [149.0 mmHg] and cognitive normal [143.7 mmHg]. After adjusting for sex, age, education, living alone, body mass index, anxiety, depression, heart disease, diabetes, and stroke, the likelihood of having dementia was positively associated with history of hypertension (odds ratio = 2.10), duration of hypertension (odds ratio = 1.02 per increment year), higher SBP (odds ratio = 1.14 per increment of 10 mmHg), higher DBP (odds ratio = 1.22 per increment of 10 mmHg), moderate hypertension (odds ratio = 2.09), or severe hypertension (odds ratio = 2.45).

Link: https://doi.org/10.3389/fneur.2018.00664

Today I'll point out a commentary on recent research in which a method of degrading mitochondrial function was shown to produce aspects of accelerated aging in mice. The commentary is somewhat more approachable than the paper it comments on. The challenge here is the same as in any form of research in which something vital is broken in animal biochemistry, and wherein the result looks a lot like a faster pace of aging. These forms of artificial breakage are almost never relevant to the understanding of normal aging; they create an entirely different state of metabolism and decline.

It is true that normal aging is a process of damage accumulation and reactions to that damage. But it is a specific mix of damage of specific types. That damage has the downstream consequence of loss of cell and tissue function, which in turn leads to the visible, well-known symptoms of aging and age-related disease. Near any form of significant damage and breakage in biochemistry will also lead to loss of cell and tissue function, however, even if it doesn't normally occur in the wild. Very high levels of unrepaired nuclear DNA damage, far greater than exist in normal animals, produce conditions that look a lot like accelerated aging. Consider Hutchinson-Gilford progeria syndrome as a natural example. But this doesn't tell us much about normal aging despite the fact that lower levels of nuclear DNA damage are a feature of normal aging.

In the research referenced in the commentary here, mitochondrial DNA is removed from cells, leaving them with an abnormally low count of genome copies in the mitochondrial population. The result looks a lot like accelerated aging. Mitochondria are the power plants of the cell, responsible for producing the chemical energy store molecules used to power all cellular processes. Progressive loss of function in mitochondria is implicated in aging and many age-related diseases, but just as in the case of raised levels of nuclear DNA damage, it isn't at all clear that artificial breakage of mitochondria tells us anything useful about the mitochondrial contribution to normal aging. It definitely tells us what happens when you break things, but any other insights are tenuous and highly dependent on the details.

Mitochondrial DNA keeps you young

Ageing is characterized by a decline in mitochondrial function, including a reduction in TCA cycle enzymes, a decrease in the respiratory capacity, and an increase in reactive oxygen species (ROS) production, in both animal models and humans. These alterations can lead to DNA mutations, cell death, inflammation, and a reduction in stem cell function, contributing to tissue degeneration. The increase in mitochondrial DNA mutations observed in aged mitochondria from both mouse models and humans is the proposed driving force.

Mitochondrial DNA (mtDNA) is replicated by a dedicated mitochondrial DNA polymerase (DNA pol γ), whose proofreading activity has been ablated to generate a mouse model, i.e., the so-called "mitochondrial mutator mouse", able to introduce random mutations in mtDNA. This model displays a strong ageing phenotype, including hair loss, graying, and kyphosis, along with reduced mitochondrial respiratory complex activity and increased oxidative stress.

Researchers have recently described a novel transgenic mouse with an inducible depletion of mtDNA, i.e., the mtDNA-depleter mouse. This model carries an aspartate to alanine conversion at position 1135 of POLG1 that behaves as a dominant negative for DNA pol γ, whose expression is under the control of a Tet-responsive promoter. Doxycycline administration leads to the induction of mutant DNA pol γ that blocks mtDNA replication. As mtDNA is removed by mitophagy for recycling, the activation of the transgene leads to a reduction of more than 60% in the total mtDNA content after 2 months. As mtDNA codes the core subunits of mitochondrial respiratory complexes, a significant impairment was observed in their activity.

At the macroscopic level, the mtDNA-depleter mouse shows expected accelerated ageing, including weight loss and kyphosis, but ageing of the skin was particularly severe and characterized by hair loss, wrinkles, and pigmentation, while at the histological level, this mouse displayed hyperplastic and hyperkeratotic epidermis, degeneration of hair follicles and extensive inflammatory infiltrates. Although the model requires extensive additional characterization, histological sections of other tested tissues (considered to have a high demand for mitochondrial activity), including the liver, brain and myocardium, do not display major alterations.

How mtDNA depletion affects ageing is a rather interesting question. The extended inflammatory infiltrates suggest that mitochondria could produce ROS as ROS can act as signaling molecules for inflammasome activation; unfortunately, the author did not report measurements of oxidative stress, but cells depleted of mtDNA are usually characterized by diminished oxygen consumption and ROS production, suggesting that oxidative stress should not mediate the ageing phenotype observed here. However, the following two major consequences were observed in a cell model of mtDNA depletion using the same strategy as that used in the depleter mouse: (1) a significant rearrangement of histone acetylation due to indirect alterations in the citrate levels, and (2) a reduction in cell proliferation due to a reduction in the membrane potential and destabilization of Hif1a. While the type of epigenetic rearrangement that occurs during ageing is unclear, Hif1a depletion has been shown to lead to an accelerated aged skin phenotype in mice.

Another extremely interesting point in this study is the recovery of the phenotype. Halting doxycycline exposure led to a surprising and almost complete recovery of the mtDNA content and skin phenotype after one month. The recovery of the mtDNA content is expected since the original mtDNA was not completely exhausted. The recovery of the skin phenotype is more intriguing. The mutator mouse model provided important insight into how mitochondria can induce an ageing phenotype by affecting haematopoietic and neural stem cell self-renewal capacities. We speculate that mtDNA depletion affects epidermal stem cell function, leading to skin ageing. Although it has long been thought that stem cells do not rely on mitochondrial function (at least for ATP production), additional observations in adult stem cells from other tissues suggest that mitochondria can be fundamental for stem cell self-renewal. However, progenitor cells, which have an established dependency on mitochondrial respiration in many models, could be more sensitive to mtDNA depletion and therefore responsible for the rapid recovery.

A growing number of researchers are arguing that the term "mesenchymal stem cell" has broadened to the point of uselessness, and now serves to obscure significant differences in cell populations. This is a similar situation to that of the long-running discussion regarding very small embryonic-like stem cells, another term of art that probably lumps together a broad selection of quite different cell types. Since mesenchymal stem cells, whatever they might be in each individual case, are now widely used in therapy it seems a little more pressing to resolve questions of cell identity here, however. To what degree are varied results from treatments an outcome of failing to adequately categorize cell phenotypes and sources? Mesenchymal stem cell transplantation is a reliable way to reduce chronic inflammation, but any other outcome, such as some degree of tissue regeneration, is by no means assured.

Various populations of cells in the adult human body have been the subject of controversy since the early 2000s. Contradictory findings about these haphazardly termed 'mesenchymal stem cells', including their origins, developmental potential, biological functions and possible therapeutic uses, have prompted biologists, clinicians and scientific societies to recommend that the term be revised or abandoned. Last year, even the author of the paper that first used the term mesenchymal stem cells (MSCs) called for a name change.

Tissue-specific stem cells, which have a limited ability to turn into other cell types, are the norm in most of the adult body. Several studies indicate that the variety of cells currently dropped into the MSC bucket will turn out to be various tissue-specific cell types, including stem cells. Yet the name persists despite the evidence pointing to this, and almost two decades after questions about the validity of MSCs were first raised. A literature search indicates that, over the past 5 years, more than 3,000 research articles referring to MSCs have been published every year.

In our view, the wildly varying reports have helped MSCs to acquire a near-magical, all-things-to-all-people quality in the media and in the public mind - hype that has been easy to exploit. MSCs have become the go-to cell type for many unproven stem-cell interventions. The confusion must be cleared up. What is needed is a coordinated global effort to improve understanding of the biology of the cells currently termed MSCs, and a commitment from researchers, journal editors, and others to use more precise labels. We must develop standardized analyses of gene expression, including on a cell-by-cell basis, and rigorous assays to establish the precise products of cell differentiation in various tissues. Such efforts could put an end to lingering questions about MSC identity and function, once and for all.

Link: https://doi.org/10.1038/d41586-018-06756-9

Human skin has evolved a greater resilience to cancer than other tissue types. It is an outcome that makes a certain amount of sense, given that skin is exposed to the additional mutational burden caused by solar radiation. Researchers here investigate some of the mechanisms involved in this cancer resistance, and suggest that the level of mutational damage is high enough that potentially cancerous mutations are continually being outcompeted by other potentially cancerous mutations. It is rare for any one mutant lineage to dominate sufficiently to generate skin cancer. The goal in this sort of investigation is to find something that could potentially serve as the basis for a cancer treatment. While this is fascinating, I don't immediately see the potential for any practical use of these findings.

Non-melanoma skin cancer in humans includes two main types: basal cell skin cancer and squamous cell skin cancer, both of which develop in areas of the skin that have been exposed to the sun. Basal cell skin cancer is the most common type of skin cancer, whereas squamous cell skin cancer is generally faster growing. However, every person who has been exposed to sunlight carries many mutated cells in their skin, and only very few of these may develop into tumours. The reasons for this are not well understood.

For the first time, researchers have shown that mutated cells in the skin grow to form clones that compete against each other. Many mutant clones are lost from the tissue in this competition, which resembles the selection of species that occurs in evolution. Meanwhile, the skin tissue is resilient and functions normally while being taken over by competing mutant cells.

Scientists used mice to model the mutated cells seen in human skin. Researchers focused on the p53 gene, a key driver in non-melanoma skin cancers. The team created a genetic 'switch', which when turned on, replaced p53 with the identical gene including the equivalent of a single letter base change. This changed the p53 protein and gave mutant cells an advantage over their neighbours. The mutated cells grew rapidly, spread and took over the skin tissue, which became thicker in appearance. However, after six months the skin returned to normal and there was no visual difference between normal skin and mutant skin.

The team then investigated the role of sun exposure on skin cell mutations. Researchers shone very low doses of ultraviolet light (below sunburn level) onto mice with mutated p53. The mutated cells grew much faster, reaching the level of growth seen at six months in non-UV radiated clones in only a few weeks. However, despite the faster growth, cancer did still not form after nine months of exposure. "In humans, we see a patchwork of mutated skin cells that can expand enormously to cover several millimetres of tissue. But why doesn't this always form cancer? Our bodies are the scene of an evolutionary battlefield. Competing mutants continually fight for space in our skin, where only the fittest survive. We did not observe a single mutant colony of skin cells take over enough to cause cancer, even after exposure to ultraviolet light. Exposure to sunlight continually created new mutations that outcompeted the p53 mutations."

Link: https://www.sanger.ac.uk/news/view/skin-battlefield-mutations

The liver is the most regenerative of organs in mammals, capable of regrowing large amounts of lost tissue following injury. Its strategy for regrowth is somewhat different from that of other tissues, and somewhat different again from the mechanisms employed by species capable of proficient regeneration, such as salamanders. Evolution has produced many approaches to growth and regrowth, it seems. It may or may not be the case that researchers can find ways to make other organs behave more like the liver. I think it is far too early to say just how challenging a proposition this might be; even were there compelling mechanisms in hand and being worked on, that would be a tough prediction to make.

Meanwhile, investigative research continues. In the work noted here, researchers uncover a role for shifts in alternative splicing in liver regeneration. Alternative splicing allows for the production of different proteins from the same genetic blueprint, and is a complex enough epicycle atop all of the other complexity of cellular biochemistry to remain comparatively poorly explored in most specific cases. The researchers tie their findings to the Hippo signaling pathway, something that has attracted attention of late in the context of rejuvenation. A number of research groups are eyeing the Hippo pathway as a target for therapies that might enhance regeneration in various internal organs. This is all largely very early stage work, and it will likely be years before something emerges into the development pipeline.

Study: Damaged liver cells undergo reprogramming to regenerate

The liver is a resilient organ. It can restore up to 70 percent of lost mass and function after just a few weeks. We know that in a healthy adult liver, the cells are dormant and rarely undergo cell division. However, if the liver is damaged, the liver cells re-enter the cell cycle to divide and produce more of themselves. Using a mouse model of a liver severely damaged by toxins, researchers compared injured adult liver cells with healthy cells present during a stage of development just after birth. They found that injured cells undergo a partial reprogramming that returns them to a neonatal state of gene expression.

The team discovered that fragments of messenger RNA, the molecular blueprints for proteins, are rearranged and processed in regenerating liver cells in a manner reminiscent of the neonatal period of development. This phenomenon is regulated through alternative splicing, a process wherein exons (expressed regions of genes) are cut from introns (intervening regions) and stitched together in various combinations to direct the synthesis of many different proteins from a single gene.

"We found that the liver cells after birth use a specific RNA-binding protein called ESRP2 to generate the right assortment of alternatively spliced RNAs that can produce the protein products necessary for meeting the functional demands of the adult liver. When damaged, the liver cells lower the quantity of ESRP2 protein. This reactivates fetal RNA splicing in what is called the Hippo signaling pathway, giving it instructions about how to restore and repopulate the liver with new and healthy cells."

Alternative splicing rewires Hippo signaling pathway in hepatocytes to promote liver regeneration

During liver regeneration, most new hepatocytes arise via self-duplication; yet, the underlying mechanisms that drive hepatocyte proliferation following injury remain poorly defined. By combining high-resolution transcriptome and polysome profiling of hepatocytes purified from quiescent and toxin-injured mouse livers, we uncover pervasive alterations in messenger RNA translation of metabolic and RNA-processing factors, which modulate the protein levels of a set of splicing regulators.

Specifically, downregulation of the splicing regulator ESRP2 activates a neonatal alternative splicing program that rewires the Hippo signaling pathway in regenerating hepatocytes. We show that production of neonatal splice isoforms attenuates Hippo signaling, enables greater transcriptional activation of downstream target genes, and facilitates liver regeneration. We further demonstrate that ESRP2 deletion in mice causes excessive hepatocyte proliferation upon injury, whereas forced expression of ESRP2 inhibits proliferation by suppressing the expression of neonatal Hippo pathway isoforms. Thus, our findings reveal an alternative splicing axis that supports regeneration following chronic liver injury.

The consensus among researchers has long been that a sizable fraction of all cancers could be avoided, given more exercise, better diet, less excess fat tissue. This is even setting aside the matter of smoking and its significant relationship to cancer. The study here is notable for adopting a slightly different approach from most other analyses, and arriving at lower numbers when it comes to the risk of a poor lifestyle. Whether or not one concurs, it is worth bearing in mind that aging remains the greatest risk factor for cancer incidence.

Cancer is a numbers game, risk over time: the wrong mutation in the wrong place; a mutated cell failing to destroy itself; the immune system failing to save the day by destroying the errant cell; the local tissue environment dysfunctional enough to support cancerous growth of that cell. Live long enough and cancer will happen, even given rejuvenation therapies capable of restoring the immune system, damping down chronic inflammation, and addressing the other most important mechanisms relating to cancer. A comprehensive, robust cure for all cancer is a vital part of the planned future toolkit of longevity assurance treatments.

Excess weight, low physical activity, and unhealthy diet contribute substantially to the development of cancer. However, no information on the attributable cancer incidence is available for the general population in Germany. By applying the concept of population-attributable fractions, we estimated the incidence of cancers attributable to excess weight, low physical activity, and unhealthy diet. Our definitions of normal body weight, recommended level of physical activity and a healthy diet followed the cancer prevention guidelines of the World Cancer Research Fund. We considered all cancer types that have been shown to be related to those lifestyle factors in published meta-analyses of prospective studies comprising 5000 or more cancer cases.

Our study revealed a high prevalence of excess weight, low physical activity, and unhealthy diet among the population in Germany in the period 2008 to 2011. For the population aged 35 to 84 years in 2018 in Germany, we therefore estimated that 30,567 incident cancers will be attributable to excess weight and 27,081 to low physical activity in 2018, corresponding to 7% and 6%, respectively, of the expected total of 440,373 incident cancers in this population. 9,000 to 14,000 cancers (2-3%) will be attributable to low intakes of dietary fiber, fruit, and non-starchy vegetables and high consumption of processed meat, and some 1,000 to 2,000 cases (less than 1%) to high intakes of salt and red meat.

Link: https://doi.org/10.3238/arztebl.2018.0578

Researchers have recently provided evidence for regeneration of skin injuries in old mice to result in lesser degrees of scarring than is the case in young mice. The usual consideration of regeneration with age is that it is disrupted by rising levels of inflammation. Further, the same set of inflammatory mechanisms appear to cause the formation of inappropriate scar-like tissue in organs, the process of fibrosis that contributes to loss of function and organ failure. Finding a way to align those well established results with the data from this study should keep research groups busy for some years. Nothing is simple in mammalian biochemistry.

Organisms repair wounds using a combination of two biological processes: scar formation and tissue regeneration. Scar formation results in deposition of fibrous tissue that disrupts the original tissue architecture. Tissue regeneration results in reconstitution of the original and functional tissue architecture, including all cellular subtypes and absence of scar formation. Although amphibians regenerate lost limbs, mammals generally repair injured tissue with scar formation. However, limited examples of human tissue regeneration do exist, including adult liver regeneration, pediatric traumatic digit tip amputations, and fetal skin wounds. These examples suggest that the mechanisms mediating tissue regeneration remain conserved in mammals.

Human skin wounds invariably form scars. Aging slows the speed of skin re-epithelialization and the subsequent rate of wound repair, but the strength of re-epithelized skin remains roughly the same at any age. Researchers have observed that skin wounds in the elderly close with thinner scars. Indeed, the incidence of keloid and hypertrophic scar formation peaks in the second decade of life and decreases with age. These surprising and somewhat counterintuitive clinical observations suggest that the tissue-regenerative pathway in the skin, instead of being diminished, may be more effective in the elderly. Here we investigated the role of aging as a regulator of mammalian tissue regeneration.

We show that full-thickness skin wounds in aged but not young mice fully regenerate. This aging-induced switch between scar formation and tissue regeneration appears to be a gradual process rather than a binary decision. Exposure of aged animals to blood from young mice by parabiosis counteracts this regenerative capacity. The secreted factor, stromal-derived factor 1 (SDF1), is expressed at higher levels in wounded skin of young mice. Genetic deletion of SDF1 in young skin enhanced tissue regeneration. Our results counter the current dogma that tissue function inevitably worsens with age and uncovers potential mechanisms to explain the paradoxical effect of aging on skin tissue regeneration.

Link: https://doi.org/10.1016/j.celrep.2018.08.054

It isn't entirely fair to categorize geroscience as the worse of the two serious and considered approaches to the treatment of aging as a medical condition, the one that isn't as good as the SENS methodology of rejuvenation through repair of molecular damage. Nor is it entirely the case that geroscience aims only to modestly slow aging to gain a few years while SENS aims at radical life extension and rejuvenation of the old. It is also inaccurate to say that geroscience is concerned only with calorie restriction mimetics and other ways to induce beneficial stress responses, the manipulation of metabolism to resist aging a little better without addressing its root causes.

Yet if you pick a random point in the SENS portfolio and a random point in the geroscience portfolio, the stereotypes above are what you'll likely land upon. Unless, of course, you happened to touch on some portion of the growing interest in senolytics, the selective destruction of senescent cells. This is the major area of overlap between the two at the present time, or - if you choose to look at things the way I do - the most prominent example of the way in which SENS will eventually take over the mainstream of research because it is demonstrably more effective. Senolytics has become a focus for an increasing fraction of the research community as the positive data continues to roll in, and justifiably so. Larger, more reliable effects are what is desired by everyone. Sadly it remains the case that most researchers and sources of funding still need to be persuaded to put aside their geroscience work in favor of the better SENS approach.

The S. Jay Olshansky article I noted a few days back is one of a few interesting position papers from a recent edition of the Journal of the American Medical Association focused on geroscience as an endeavor. The other two are noted below, and each is worth reading as a standalone piece. The bigger picture is that the tenor of the great cultural conversation about aging is changing, has changed significantly, is no longer what it was even a decade ago. The technologies that slow and reverse aging are starting to emerge and be demonstrated in ways that cannot be refuted. Treating aging as a medical condition is no longer mocked in the media - the serious people are convinced. The future is arriving.

Aging as a Biological Target for Prevention and Therapy

Chronic health problems related to the unprecedented aging of the human population in the 21st century threaten to disrupt economies and degrade the quality of later life throughout the developed world. Fortunately, research has shown that fundamental aging processes can be targeted by nutritional, genetic, and pharmacologic interventions to enhance and extend both health and longevity in experimental animal models. These findings clearly demonstrate that the biological rate of aging can be slowed.

The geroscience hypothesis, for which there is abundant evidence in animal models, links these biological discoveries to human health by proposing that targeting biological aging processes will prevent, or at a minimum delay, the onset and progression of multiple chronic diseases and debilities that are typically observed in older adults. For example, interventions that extend the life span of mice often also prevent or slow the progress of several types of cancer, reduce atherosclerotic lesions, improve heart function, alleviate normal age-related cognitive loss, and even improve vaccine response.

One of the main geroscience accomplishments is to highlight a small number of major "pillars," interacting molecular and physiological processes that underlie the biology of aging, for instance, metabolism, proteostasis, macromolecular damage, inflammation, adaptation to stress, epigenetics, and stem cells and their regeneration. The key feature of this conceptual framework is that these processes are understood to be tightly interrelated. These findings have emerged from the remarkable progress made in recent years in dissecting aging processes in model organisms. The discovery of cellular and molecular pathways that modulate healthy aging in diverse species across great evolutionary distances offers an unprecedented opportunity for intervention

Aging, Cell Senescence, and Chronic Disease: Emerging Therapeutic Strategies

Age is the leading predictive factor for most of the chronic diseases that account for the majority of morbidity, hospitalizations, health costs, and mortality worldwide. The fundamental aging processes that contribute to phenotypes characteristic of advanced old age, such as muscle weakness and loss of subcutaneous fat, also appear to underlie the major chronic diseases, geriatric syndromes, and loss of physical resilience. These aging processes can be broadly classified as follows: (1) chronic, low-grade inflammation that is "sterile" (occurring in the absence of known pathogens), together with fibrosis; (2) macromolecular and cell organelle dysfunction (such as DNA damage, dysfunctional telomeres, protein aggregation and misfolding, decreased removal of damaged proteins, or mitochondrial dysfunction); (3) changes in stem cells and progenitors that lead to reduced capacity to repair or replace tissues; and (4) cellular senescence.

Senescence involves essentially irreversible arrest of cell proliferation, increased protein production, resistance to programmed cell death (apoptosis), and altered metabolic activity. Senescent cells accumulate in multiple tissues as a result of chronological aging, especially after middle age, and in tissues central to the pathogenesis of chronic diseases. For example, senescent cells accumulate in and near bone in patients with age-related osteoporosis and in blood vessel walls in patients with vascular disease.

Some senescent cells develop a senescence-associated secretory phenotype (SASP) that entails release of proteins, bioactive lipids, nucleotides, extracellular vesicles, and other factors. The SASP contributes to inflammation and the breakdown of tissues, stem and progenitor cell dysfunction, and the spread of senescence to nonsenescent cells. The SASP, immune cells attracted and activated by the SASP, and spread of senescence contribute to profound local and systemic effects with even small numbers of senescent cells. For example, transplanting small numbers of senescent cells around knee joints in young mice leads to joint pain and pathologic changes closely resembling human osteoarthritis. Transplanting senescent cells into middle-aged mice so that only 1 in 10,000 cells in the recipients is a transplanted senescent cell is sufficient to cause profound physical dysfunction within 2 months, together with early death due to accelerated onset of age-related diseases as a group, compared with transplanting nonsenescent cells.

Intermittent fasting, particularly in the form of fasting mimicking diets that enhance autophagy and last long enough to trigger significant reduction and replacement of immune cells, is growing in popularity as a way to activate the range of cellular stress responses known to modestly improve health. It isn't the only way to alter behavior and the environment to upregulate beneficial cellular stress responses such as autophagy, however. Thus the authors of this open access paper propose that a broader program of periodic challenges should be introduced as a best practice for human health, and be as strongly recommended as regular exercise. The health benefits may be in the same ballpark. They choose to call this "intermittent living." A great deal of gathering and analysis of data lies between here and the realization of their vision, of course.

The number of people with chronic diseases such as cardiovascular diseases (CVD), diabetes, respiratory diseases, mental disorders, autoimmune diseases and cancer has increased dramatically over the last three decades. The increasing rates of these chronic systemic illnesses suggest that inflammation, caused by excessive and inappropriate innate immune system activity, is unable to respond appropriately to danger signals that are new from the perspective of evolution.

These, mostly environment-driven, risk factors seem inevitable in current Western societies and their shares and intensities are most likely destined to further increase in the future. Importantly, many of these risk factors exhibit interaction, while contemporary humans are likely to suffer from these challenges in concert. This contrasts with the stress factors experienced by traditionally living populations who still live in the environment of our ancestors. In that environment, they had to cope with short-term mono-metabolic danger factors (e.g. hunger, thirst, cold, heat), whereas modern humans are exposed to multi-metabolic risk factors that stimulate an energy conflict between organs and major systems. The ensuing conflict between current experience and to what our genes and stress systems are adapted is the basis of the so-called 'mismatch hypothesis' of 'typically Western' diseases.

Mono-metabolic stress factors have shaped adaptive mechanisms for survival and reproduction, such as short-lasting inflammation, insulin resistance, activation of the sympathetic nervous system and others. Mild triggers might at least in part reset physiologic and metabolic dysfunctioning in patients with 'typically Western' diseases. In other words they may provide low-cost opportunities for secondary prevention. Conversely, the chronic absence of mild stress factors may have rendered modern 21st century humans less resistant to major toxic insults and susceptible to the development of many, 'typically Western', chronic diseases of affluence, including metabolic disorders.

Several of our studies showed that the combination of certain intermittent stress factors produce a hormetic early stress response with a compensatory improvement of multiple metabolic and immunological indices, and wellbeing. The employed hormetic triggers included: intermittent fasting, intermittent heat, intermittent cold, intermittent hypoxia, intermittent drinking, and the consumption of a great number of nutrients with hormetic effects. The use of intermittent challenges, combined in a homework-protocol, could serve as a vaccine against the deleterious effects of modern life. We named this concept "intermittent living", defined as the daily intermittent use of known ancient triggers for a period of seven days per month. We propose to use this concept as a basis for interventions for individuals with chronic disease and/or its prevention. Intermittent living is no more than the reintroduction of mild environmentally-based short lasting stress (including cold, heat, hunger, thirst).

Link: https://doi.org/10.1016/j.mehy.2018.08.002

Considerable effort in the research community is devoted to the search for small molecule drugs that can break down or inhibit formation of the protein aggregates associated with various forms of neurodegenerative disease. One of these is α-synuclein, a prominent feature of Parkinson's disease. Potential treatments based on clearance of α-synuclein are at varying points in the development and regulatory approval pipeline. The materials here provide one of many examples of continued efforts to produce new drug candidates that can enter that pipeline. This is an uncertain process: scanning the compound libraries for new possibilities has unknown (but certainly low) odds of success in any given case. It is expensive and slow besides, and few sources of funding are willing to roll the dice given those points.

Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons, a process that current therapeutic approaches cannot prevent. In PD, the typical pathological hallmark is the accumulation of intracellular protein inclusions, known as Lewy bodies and Lewy neurites, which are mainly composed of α-synuclein. Recently, we have developed an accurate and robust high-throughput screening methodology to identify α-synuclein aggregation inhibitors. Here, we exploited this methodology to identify a small molecule (SynuClean-D) able to inhibit α-synuclein aggregation.

SynuClean-D significantly reduces the in vitro aggregation of wild-type α-synuclein and familiar variants in a substoichiometric molar ratio. This compound prevents fibril propagation in protein-misfolding cyclic amplification assays and decreases the number of α-synuclein inclusions in human neuroglioma cells. Computational analysis suggests that SynuClean-D can bind to cavities in mature α-synuclein fibrils and, indeed, it displays a strong fibril disaggregation activity. The treatment with SynuClean-D of two PD Caenorhabditis elegans models, expressing α-synuclein either in muscle or in dopaminergic neurons, significantly reduces the toxicity exerted by α-synuclein.

SynuClean-D-treated worms show decreased α-synuclein aggregation in muscle and a concomitant motility recovery. More importantly, this compound is able to rescue dopaminergic neurons from α-synuclein-induced degeneration. Overall, SynuClean-D appears to be a promising molecule for therapeutic intervention in Parkinson's disease.

Link: https://doi.org/10.1073/pnas.1804198115

It is fairly settled in the scientific community, barring the odd few objections here and there, that regular moderate exercise improves health in the long term, relative to a sedentary lifestyle. When it comes to the details of the dose-response curve for exercise, however, the scientists of the field are still somewhere in the midst of a slow and grand debate that has lasted decades and seems likely to last for decades more. Extracting solid conclusions from human epidemiological data is a challenging endeavor at the best of times. The papers noted below are illustrative of a score or more similar efforts published every year, as researchers add ever more analysis to the existing mountain of thought on exercise and health.

Present evidence is leaning in the direction of a big leap in benefits in the transition from no exercise and minimal physical activity. Benefits increase thereafter up to the point of an hour or so a day, and then may or may not decline with further increases. Clearly there is a point at which too much exertion is harmful, but does that occur prior to the level of exercise undertaken by profession athletes? If so, how to account for their longevity compared to the rest of the population? It may be that people who can become professional athletes are just more robust than everyone else to start with, or alternatively it has to do with social status, wealth, and other confounding factors.

Further, even if there ever comes to be solid agreement on how much exercise is best, what about the different forms of exercise? Are repeated short bursts better or worse than extended effort? Can short term effects be separated from long term effects? Is strength training so important as to be worth sacrificing time on aerobic exercise to undertake it? Is cycling better or worse than rowing? Or swimming? Or moving plants around the garden? An endless series of questions might be posed. Few of them will be definitively answered before we find ourselves in an era in which optimizing the effects of exercise is an amusing hobby and little more, because rejuvenation biotechnologies exist. Their effects on health and life span will far exceed anything that might be produced by finding a way to do a little better than the currently recommended level of exercise.

The Goldilocks Zone for Exercise: Not Too Little, Not Too Much

Homo sapiens are evolutionarily adapted to be very physically active throughout life, and thus habitual physical activity (PA) is essential for well-being and longevity. Never the less, middle-aged and older individuals engaging in excessive strenuous endurance exercise appear to be at increased risk for a variety of adverse cardiovascular effects including atrial fibrillation, myocardial fibrosis, and coronary atherosclerosis. An emerging body of evidence indicates U-shaped or reverse J-shaped curves whereby low doses and moderate doses of PA significantly reduce long-term risks for both total mortality and cardiovascular mortality, however, at very high doses of chronic strenuous exercise much of the protection against early mortality and cardiovascular disease is lost.

The optimal dose, or what we term 'Goldilocks Zone,' of PA may be: at least 150 minutes per week of moderate-intensity aerobic exercise or 75 minutes per week of vigorous-intensity aerobic activity, but not more than four to five cumulative hours per week of vigorous (heart-pounding, sweatproducing) exercise, especially for those over 45 years of age. It is also important to take at least one day per week off from vigorous exercise. There appears to be no concerns about an upper threshold for safety for leisure-time low-to-moderate intensity activities such as walking at a comfortable pace, housework, gardening, etc. After every 30 consecutive minutes spent sitting, stand up and move, ideally walking briskly for about five minutes.

Now you just need to remember to exercise!

In a study of 36 healthy young adults, the researchers discovered that a single 10-minute period of mild exertion can yield considerable cognitive benefits. Using high-resolution functional magnetic resonance imaging, the team examined subjects' brains shortly after exercise sessions and saw better connectivity between the hippocampal dentate gyrus and cortical areas linked to detailed memory processing. "The hippocampus is critical for the creation of new memories; it's one of the first regions of the brain to deteriorate as we get older - and much more severely in Alzheimer's disease. Improving the function of the hippocampus holds much promise for improving memory in everyday settings."

While prior research has centered on the way exercise promotes the generation of new brain cells in memory regions, this new study demonstrates a more immediate impact: strengthened communication between memory-focused parts of the brain. "We don't discount the possibility that new cells are being born, but that's a process that takes a bit longer to unfold. What we observed is that these 10-minute periods of exercise showed results immediately afterward."

Mitochondrial changes similar in short sprint exercise versus longer moderate-intensity workouts

A team of researchers studied eight young adult volunteers as they participated in cycling workouts of varying intensity: (a) moderate intensity consisted of 30 minutes of continuous exercise at 50 percent peak effort; (b) high-intensity interval exercise consisted of five four-minute cycling sessions at 75 percent peak effort, each separated by one minute of rest; (c) sprint cycling consisted of four 30-second sessions at maximum effort, each separated by 4.5 minutes of recovery time.

The research team measured the amount of energy the volunteers spent on each workout and compared mitochondrial changes in the participants' thigh muscles before and after each exercise session. The researchers found that fewer minutes of higher-intensity exercise produced similar mitochondrial responses compared to a longer moderate-intensity activity. "A total of only two minutes of sprint interval exercise was sufficient to elicit similar responses as 30 minutes of continuous moderate-intensity aerobic exercise. This suggests that exercise may be prescribed according to individual preferences while still generating similar signals known to confer beneficial metabolic adaptions."

Lifespan.io has launched their latest crowdfunded study, and seeks more donors to join the more than 100 philanthropists of our community who have pledged already in the first few days. It is an assessment of the capacity of nicotinamide mononucleotide (NMN) to slow aging in mice, treating both normal mice and a lineage exhibiting accelerated aging. The final stretch goal in this fundraiser will provide enough funding to kick off a full life span study. This work is carried out in partnership with David Sinclair's lab, home of the past fifteen years of work on calorie restriction mimetics associated with sirtuins, a line of research that has evolved to these days to focus instead on nicotinamide adenine dinucleotide, NAD+.

NMN is one of a number of options that can be used to treat the loss of NAD+ in older individuals. While this approach doesn't address any of the causes of aging, meaning the rising levels of molecular damage that take throughout the body, it does serve to boost mitochondrial function. Mitochondrial function is well known to falter with age, and researchers consider this important in a range of age-related conditions. The evidence to date suggests that enhancing NAD+ levels may to some degree diminish measures of aging. To pick one recent example from the data, a small human trial of nicotinamide riboside, another of the options to raise NAD+ levels, demonstrated a reduction in blood pressure in hypertensive older patients.

One of the best studied anti-aging treatments is a diet reduced in calories, yet high enough in nutrients to avoid malnutrition. Known as calorie restriction (CR), this dietary regimen provides irrefutable evidence of the importance of metabolism in the aging process. While CR has been studied extensively and even tested in human trials, long term adherence to a CR dietary regimen is extremely difficult for most individuals to maintain.

One method to achieve the benefits of CR for everyone would be to administer compounds which act as "CR mimetics". A major metabolic signaling molecule that we and others have shown to exhibit significant declines with increasing age is NAD+. Importantly, CR reverses the age-related decline of bioavailable NAD+. This key metabolite plays a crucial role in regulating the activity of many important signaling molecules involved in age-related diseases.

However, feeding or administering NAD+ directly to organisms is not a practical option. The NAD+ molecule cannot readily cross cell membranes to enter cells, and therefore would be unavailable to positively affect metabolism. Instead, precursor molecules to NAD+ must be used to increase bioavailable levels of NAD+. Recently, we have shown that by administering the NAD+ precursor NMN (Nicotinamide Mononucleotide) in drinking water to older mice, NAD+ levels were restored to those normally associated with younger healthy animals. By administering NMN to mice for just one week, our lab demonstrated a robust correction in age-associated metabolic dysfunction and restored muscle mitochondrial function in old mice to levels seen in younger control mice.

Although the restorative properties of NMN treatment drive many of the same cellular signaling pathways which underlie CR, trials of greater than one week or two months are needed to properly evaluate whether NMN can reverse the aging process. Starting with mice that are 20 months old (roughly equivalent to a 50 year old human), longer-term NMN treatments will be applied in order to restore levels of cellular NAD+ to those found in youthful mice. Along with a large cohort of normal mice, we will also use a cohort of our novel genetically engineered mouse, termed the ICE mouse (Induced Changes In Epigenome). These ICE mice manifest an accelerated aging phenotype.

Your donations will not only allow us to purchase the materials necessary to perform this experiment, but also pave the way for human clinical trials aimed at showing, for the first time, that we can actually slow down human aging. We find ourselves at a turning point in history, and together we have the chance to accelerate technologies that will allow us to live healthfully at any age. This is a future that is coming, and whether it arrives in our lifespan or only for future generations is up to us.

Link: https://www.lifespan.io/campaigns/can-nmn-increase-longevity/

The herd of bacteria-like mitochondria in each of our cells are vital cellular components, and come equipped with their own small genome, the mitochondrial DNA, one or more copies in each mitochondrion. If that DNA is broken, then harm results. Mitochondrial diseases bear only superficial similarities to the mitochondrial DNA damage that is a root cause of degenerative aging; while it is the case that mitochondrial DNA is mutated in both cases, the distribution of those mutations in cells and tissues is quite different. Nonetheless, it seems a reasonable proposition that a strategy of selectively destroying damaged mitochondrial DNA may work in each situation, though for different reasons.

In inherited mitochondrial disease, there is some split between healthy and damaged copies of mitochondrial DNA in cells. Destroy the bad genome copies and the good ones will hopefully replicate to make up that loss. In aging, just a few cells become entirely overtaken by clones of mitochondria with damaged genomes, but they exert a sizable negative influence on health via generation of oxidative molecules. Destroying all of the mitochondrial DNA in those cells might be expected to kill them, for all of the obvious reasons. Since there are few of them, destroying them is probably the most expedient approach to dealing with the issue. In both cases, effectiveness would be determined by how clean a sweep is made, though one might imagine temporary or partial benefits resulting from removing even half of the damaged mitochondrial genomes.

"Mitochondrial replacement therapy is a promising approach to prevent transmission of mitochondrial diseases, however, as the vast majority of mitochondrial diseases have no family history, this approach might not actually reduce the proportion of mitochondrial disease in the population. One idea for treating these devastating diseases is to reduce the amount of mutated mitochondrial DNA by selectively destroying the mutated DNA, and allowing healthy DNA to take its place."

To test an experimental gene therapy treatment, which has so far only been tested in human cells grown in petri dishes in a lab, the researchers used a mouse model of mitochondrial disease that has the same mutation as some human patients. The gene therapy treatment, known as the mitochondrially targeted zinc finger-nuclease, or mtZFN, recognises and then eliminates the mutant mitochondrial DNA, based on the DNA sequence differences between healthy and mutant mitochondrial DNA. As cells generally maintain a stable number of mitochondrial DNA copies, the mutated copies that are eliminated are replaced with healthy copies, leading to a decrease in the mitochondrial mutation burden that results in improved mitochondrial function.

The treatment was delivered into the bloodstream of the mouse using a modified virus, which is then mostly taken up by heart cells. The researchers found that the treatment specifically eliminates the mutated mitochondrial DNA, and resulted in measures of heart metabolism improving. Following on from these results, the researchers hope to take this gene therapy approach through clinical trials, in the hope of producing an effective treatment for mitochondrial diseases.

Link: https://www.cam.ac.uk/research/news/mitochondrial-diseases-could-be-treated-with-gene-therapy-study-suggests