Nitric oxide is present in many areas of metabolism that change with aging or that influence the pace of aging. Calorie restriction results in increased nitric oxide levels, for example, though as always researchers are far from putting all the pieces of the calorie restriction response together in a neat arrangement of cause and effect. Nitric oxide levels are thought to influence mitochondrial activity and stem cell populations as well, and both of those are important in aging. There is interest in trying to manipulate nitric oxide mechanisms in efforts to slow the progression of aging:

Nutrition and medical advancements leading to increased lifespan are not adequately translating into improved healthspan. Present-day gerontology research suggests that, unlike traditional approaches that focus on specific diseases, deciphering, and targeting the aging process itself could be the most clever approach toward increased healthspan.

Multiple cell effectors work together to cause the senescent cell phenotype. Particularly, two cellular organelles - nucleus and mitochondrion - have been implicated in the "wear and tear" aspects of aging. Nitric oxide (NO) generated through the endothelial nitric oxide synthase (eNOS) acts to promote mitochondrial biogenesis and bioenergetics, with a favorable impact in diverse chronic diseases of the elderly. Obesity, diabetes and aging share common pathophysiological mechanisms, including mitochondrial impairment and dysfunctional eNOS. Here we review the evidences that eNOS-dependent mitochondrial biogenesis and quality control, and possibly the complex interplay among cellular organelles, may be affected by metabolic diseases and the aging processes, contributing to reduce healthspan and lifespan.

Though still in its infancy, research on the role of the eNOS-NO system in the control of cell organelle connections and quality control might reveal exciting avenues for disease treatment in the coming years. The development of novel therapies aiming to preserve eNOS-NO signaling will benefit from the identification of site-specific interaction with the eNOS structure. Drugs or nutrients able to sustain the eNOS-NO generating system might contribute to maintain organelle homeostasis and represent novel preventive and/or therapeutic approaches to chronic age-related diseases. Efforts to identify druggable eNOS sites are ongoing, although our knowledge about the therapeutic usability of the proposed eNOS-targeting molecules in the long-term is limited.

Link: http://journal.frontiersin.org/article/10.3389/fcell.2015.00006/full

This article goes into some detail on recent research into whether retrotransposons in the genome play a meaningful role in aging. This is analogous to the debate over whether stochastic nuclear DNA damage has a role in aging beyond causing cancer, and the sort of studies you'd need to introduce clear proof one way or another are much the same:

Retrotransposons, often referred to as jumping genes, are mobile genetic elements that parasitize host machinery to replicate themselves across the genome. Since their emergence more than 100 million years ago, retrotransposons have been enormously successful. Modern mammalian genomes, for example, are riddled with the scars of these copy-and-paste events, with retrotransposon-derived DNA now accounting for nearly 50 percent of the human genome.

The most dangerous retrotransposon in mammalian genomes is the long interspersed nuclear element-1 (LINE-1 or L1). L1 retrotransposons are a little more than 6 kilobases long and encode an RNA-binding protein and an endonuclease with reverse-transcriptase activity that allow the element to autonomously replicate in the host genome via an RNA intermediate. The human genome contains more than 500,000 copies of L1s. Although the vast majority of these have been inactivated as a result of truncation, mutation, and internal rearrangement, it is estimated that approximately 100 of these L1s per nuclear genome still retain their replication activity. Despite their abundance, however, L1s are not benign. Rather, their activity, and even their presence, represents a real danger to the host, increasing the risk of DNA damage, cancer, and other maladies. Given the consequences of L1 activity, it is unsurprising that host genomes devote considerable resources to suppressing these retrotransposons. Indeed, every step of the L1 life cycle is impeded in some way by host factors such as gene silencing, antiviral defense machinery, small RNAs, and autophagy.

Historically, little attention has been given to retrotransposition in somatic tissue, because this was thought of as an evolutionary dead end. In recent years, however, evidence has accumulated that L1 elements can become active in a variety of somatic tissues in humans and mice, including in the brain, skeletal muscle, heart, and liver. Intriguingly, some of the highest L1 activity has been observed in aging tissues, particularly those affected by age-related pathologies such as cancer. This raises the interesting possibility that L1 activity may contribute to the aging process. Increased DNA damage and mutagenesis are prevalent in aging tissues, and L1 activity is known to increase following such damage. In addition, a small number of studies have shown that overexpression of L1 can cause cells to senesce, a hallmark of aging tissues. The role of L1 in driving age-related processes is now a topic ripe for study.

Link: http://www.the-scientist.com/?articles.view/articleNo/42274/title/Wrangling-Retrotransposons/

The Movement for Indefinite Life Extension (MILE) is one of a number of grassroots initiatives in which ordinary folk like you or I are doing their part to help raise awareness and funding for rejuvenation research. Every great journey is made one small step at a time, and the tipping point at which the public at large begins to accept and supports longevity science in the same way as is the case for cancer research today will be crossed by one such modest effort among many. The community of people who understand and support efforts to bring an end to degenerative aging through medical science grows and diversifies as the years pass. The more of us there are the more that we can do to help advance research and educate the public. There is a role for everyone in this, and at all levels of effort, whether it is donating millions to establish a new research program or persuading a few of your friends that it's pretty silly to be for cancer research but against a cure for all age-related frailty and disease.

MILE is organizing an online demonstration on March 21st to coincide with live meetups in Chicago, Los Angeles, and Washington D.C. I was asked to provide a poster or two, and so bearing in mind that this is a demonstration I ran up something very simple that should be legible at distance. Less is more for this sort of thing, and it is easy enough to cut and paste other taglines and URLs. The font is Liberation Sans Bold, but any generic sans-serif font works just fine at this size.

Support Rejuvenation Research Poster: 4200 x 2800px

Fund More Research Poster: 4200 x 2800px

The liver is the most regenerative of organs in mammals, capable of regrowing much of its mass. That is arguably less important than the ability of a complete liver to regenerate the damage of aging and disease, such as growing fibrosis and dysfunction in cell populations necessary for organ function. Deployment of therapies to reliably achieve this goal still lies ahead, but researchers are making slow progress in the right direction:

The liver possesses extraordinary regenerative capacity in response to injury. However, liver regeneration is often impaired in disease conditions. Wild-type p53-induced phosphatase 1 (Wip1) is known as a tumor promoter and enhances cell proliferation mainly by deactivating anti-oncogenes. However, in this work, we identified an unexpected role of Wip1 in liver regeneration. In contrast to its known role in promoting cell proliferation in extra-hepatic tissue, we found that Wip1 suppressed hepatocyte proliferation after partial hepatectomy (PH). Deletion of Wip1 increased the rate of liver regeneration following partial hepatectomy.

The enhanced liver regeneration in Wip1 deficient mice was due to the activation of mammalian target of rapamycin complex 1 (mTORC1) pathway. Furthermore, we showed that Wip1 physically interacted with and dephosphorylated mammalian target of rapamycin (mTOR). Interestingly, inhibition of Wip1 also activated p53 pathway during liver regeneration. Disruption of the p53 pathway further enhanced the liver regeneration in Wip1 deficient mice. Therefore, inhibition of Wip1 has a dual role in liver regeneration, i.e. promoting hepatocyte proliferation via activation of mTORC1 pathway, meanwhile suppressing liver regeneration through activation of p53 pathway.

For the first time we demonstrate that mTOR is a new direct target of Wip1. Wip1 inhibition can activate the mTORC1 pathway and enhance hepatocyte proliferation after hepatectomy. Therefore, our findings have clinical applications in cases where liver regeneration is critical, including acute liver failure, cirrhosis or small-for-size liver transplantations.

Link: http://dx.doi.org/10.1002/hep.27755

Regular readers know that significant progress towards human rejuvenation, ending frailty and disease in aging, requires that SENS research, or something very like it, disrupts the present status quo to become the scientific mainstream in this field. SENS is focused on periodic repair of the fundamental damage to cells and macromolecules that occurs as a side-effect of the ordinary operation of metabolism. A strong focus here is on the accumulation of metabolic byproducts such as amyloids, lipofuscin and cross-links, while in comparison age-related changes in telomere biochemistry and epigenetic patterns are not all that important as targets: changes there are secondary effects, and thus should be reversed if the underlying damage is repaired.

In comparison the mainstream high level research strategy for aging and longevity is the other way around for these areas; there is comparatively little concern with metabolic byproducts as a target for treatment outside of the Alzheimer's field, and a great deal of interest in targeting telomeres and epigenetic changes. In general this is driven by a philosophy of metabolic alteration: the guiding principles are to (a) find ways to change the operation of metabolism to slow down the accumulation of damage and thus slow aging, or (b) force metabolic control processes back into a youthful configuration. This is a far worse approach than damage repair; it cannot produce rejuvenation, and in many cases ignores the root causes of aging while trying to force damaged biochemistry to behave as though it were not damaged and aged. We should expect only marginal outcomes from such efforts.

Both SENS and the present mainstream overlap in their concern for cancer and stem cell function. Both consider mitochondrial function important in aging, but with important differences in the present consensus of how and why it is important, and what should be done as a result. In the SENS vision, stochastic nuclear DNA damage is probably not all that important outside of cancer, but the mainstream consensus is that it probably is a cause of age-related disregulation of cellular activities and tissue function. This article reflects the mainstream view:

Age is the number one risk factor for myriad diseases, including Alzheimer's, cancer, cataracts, and macular degeneration. And while researchers are making progress in understanding and treating each of these ailments, huge gaps remain in our understanding of the aging process itself. The aging process can be traced down to the level of cells, which themselves die or enter senescence as they age, and even to the genomic level. Accumulation of mutations and impairments in DNA repair processes are highly associated with symptoms of aging. In fact, disorders that cause premature aging are typically caused by mutations in genes involved in the maintenance of our DNA. And at the cellular level, decreases in stem cells' proliferative abilities, impairments in mitochondrial function, and proneness to protein misfolding can all contribute to aging. As scientists continue to detail these various processes, the big question is, "At what step along all these pathways is the best place to intervene to try to promote healthy aging? The therapeutic goal would be to increase health span, not life span. There's nothing fun about living to be really old if your health diminishes to the point that it's no longer fun to be alive."

As DNA replicates, the cellular machinery involved in the process makes mistakes, leading to changes in the DNA sequence. While it's unclear exactly how DNA damage contributes to aging, what's certain is that the damage and mutations contribute to cancer, "There is this exponential increase in cancer risk during aging, so it's not at all unlikely . . . that accumulation of damage to the genome is really a major factor here." Premature-aging diseases in humans also point to the role of DNA repair and stabilization mechanisms in the aging process. But how DNA damage leads to aging in normal adults remains an open question.

Epigenetic marks shift over time in a variety of healthy cells. Indeed, mapping of DNA methylation in human cells has shown that some areas of the genome become hypermethylated with age, while others show reduced methylation. Histone modifications, another type of epigenetic mark, have also been shown to change with age in some human tissues. The question now is whether these epigenetic changes influence aging. "Is this an epiphenomenon that happens just because we age, or is it actually causing symptoms or diseases of aging and limiting life span?"

A particularly influential form of DNA damage occurs at telomeres, the repetitive sequences that cap chromosomes and shorten with age. While germ and stem cells express an enzyme called telomerase that replenishes telomeres, most cells' telomeres shrink with every division, due to the fact that DNA polymerase cannot fully replicate the ends of chromosomes. If the telomeres shrink too much or are damaged, cells undergo apoptosis or enter senescence. Telomere damage has clear effects on aging. Mice with short telomeres have diminished life spans and reduced stem-cell and organ function, while mice whose telomerase is enhanced in adulthood age more slowly.

Life depends on proper protein function. And proper protein function is all about proper protein folding. Misshapen proteins are often rendered useless and can clump together with other misfolded proteins inside cells. It is not yet clear whether protein misfolding leads to aging, but it appears that it is an almost inevitable physiological reality that the two coincide. To add insult to injury, advancing age also brings about the decline of molecular chaperones that aid in the folding process and of protective pathways that normally help clear misfolded proteins from cells. "The big open question is whether the accumulation of misfolded protein aggregates is the cause or consequence of the aging process. The hypothesis is that maybe there is a widespread accumulation of misfolded protein aggregates affecting all cells in the body, and that produces progressive dysfunction of cells in the body that leads to aging."

There is a new view of oxidative damage to mitochondria. "If damage is not too severe, there's some sort of protective response. What won't kill you makes you stronger." There is a limit to how much damage the organelle can handle, however, and mitochondrial dysfunction may well contribute to aging. "It's consistent with this idea that maybe from metabolism you get oxidative stress, you then get DNA damage, then that decline in mitochondrial function makes us age." Mitochondria's role in aging is likely not limited to oxidative or even DNA damage. Given the organelles' broad-reaching involvement in metabolism, inflammation, and epigenetic regulation of nuclear DNA. "They may be central integrators of many of the pathways we've implicated in aging."

Healthy adults produce about 200 billion new red blood cells each day to replace the same number removed from circulation every 24 hours. But the rate of blood-cell production declines with age. "It's a bit of a mystery as to why these self-renewing cells in different tissues stop working. The nature of molecular aging at the cellular level is not fully known." Researchers have also linked epigenetic alterations, such as locus-specific changes in DNA methylation, to the reduced regenerative capacity of stem cells with age. And age-related shifts in the environment in which stem cells divide and differentiate, dubbed the stem-cell niche, may also contribute to stem-cell aging. Exactly why and how stem cells slow down with age is still a mystery.

Stem cells and other cells that undergo damage and decline do not age in isolation. Researchers are finding that some processes of aging influence the release of regulators that circulate in the blood. "At one time, everybody thought, well, cells just get old and die. But the cells do more than just die. They do negative things, and they persist." One such regulator is growth differentiation factor 11 (GDF11), which measurably decreases with age. Researchers found that young blood can restore some lost functions in the hearts, brains, and skeletal muscles of older mice, and that these effects can be replicated by treating old mice with GDF11. The researchers are now working to pinpoint the sources of circulating GDF11, as well as to understand the mechanisms by which it remodels aging tissues.

Many of the questions voiced in the article could be answered most cost-effectively by implementing the SENS research programs to the point of demonstrating all of the repair biotechnologies in mice, and then observing the results. At this time it is estimated that the cost of doing so is about a decade of time and perhaps a billion dollars; this is about the same cost as is incurred in the development of a single new drug. It seems well worth doing.

Link: http://www.the-scientist.com/?articles.view/articleNo/42280/title/How-We-Age/

The extracellular matrix (ECM) is the complex structure of proteins surrounding and supporting cells. The varied mechanical properties of different tissues derive from the particular arrangement and types of molecules making up this structure: the elasticity of skin and blood vessels, the load bearing resilience of bone and cartilage, and so forth. Some of the fundamental forms of cellular and molecular damage that cause aging produce degenerative effects through changes to the extracellular matrix that degrade its properties. For example, cross-links formed by sugary metabolic waste glue together structural proteins. The most persistent types of cross-link accumulate over the years and their presence contributes to the loss of elasticity in skin and blood vessel walls, as well as to the growing fragility of bones in the elderly.

A different type of problem is caused by senescent cells, which have removed themselves from the cell cycle in response to damage or a potentially damaging local tissue environment. Senescent cells adopt what is known as a senescent-associated secretory phenotype, releasing a mix of compounds that encourage other nearby cells to become senescent, but which also degrade or restructure the surrounding extracellular matrix. Cellular senescence may be a repurposed tool of embryonic development, a mechanism that helps shape growing organs, and its activities in attacking the extracellular matrix are a holdover from that role. Whether or not this is the case, senescent cells are destructive and degrade the structural properties of the extracellular matrix where they gather in numbers.

Both senescent cells and cross-links could be dealt with in the very near future, removing and reversing their contributions to degenerative aging, given sufficient funding for research. Selective destruction of senescent cells has been demonstrated in principle, and a few research groups are working on different approaches to making a therapy of this approach. On the cross-link side of the house, the single most important type of cross-link in humans is formed of a single compound, glucosepane. Thus drug development has a single target to hit: all it takes is for the tools to be produced and for one laboratory to find a good drug candidate. This work is also underway in the early stages, carried out by a few small research groups. Neither of these lines of research is anywhere near well enough funded, or appropriately funded for the size of the potential benefits, however. A sizable chunk of the presently ongoing work is funded by one organization, the SENS Research Foundation, and supported entirely by philanthropic donations. This is the story for much of the potential rejuvenation toolkit that could be built in the years ahead - but which will take much longer to realize than it might, because funding and interest are the limiting factors. This is exactly why advocacy and education for this cause are so very important.

Structural properties of tissue determined by the extracellular matrix go beyond elasticity and strength. There is also the matter of electrical properties, important in the heart and nervous system. Degradation of the extracellular matrix in heart tissues and its impact on the heart's electrical conduction system is probably a contributing factor the increased prevalence of arrhythmias and similar issues with advancing age.

The role of extracellular matrix in age-related conduction disorders: a forgotten player?

Prevalence of cardiac arrhythmias increases over time during aging, carrying significantly higher morbidity and mortality in the elderly. Defective impulse generation and conduction and ECM disarray with augmented intramyocardial fibrosis during aging are considered the main biological processes responsible of these disturbances.

In this context, in spite of the interest addressed by the literature to the "aged cardiomyocyte" as the main pathological responsible of age-related conduction disturbances, there are several lines of evidence pointing at changes in the structure and function of the extracellular matrix (ECM) as an important actor. At the biophysical level, cardiac ECM exhibits a peculiar degree of anisotropy, which is responsible for the elastic and compliant properties of the ventricle and for the structural properties of heart valves. However, ECM components and their arrangement are also the main determinants of the conductive properties of the specialized electrical conduction system. Moreover, cardiac ECM is actively sending biological signals regulating cellular function and tissue homeostasis. Alterations of ECM function in the elderly might additionally exert a detrimental effect on the normal function of the conduction system and on overall ventricular function and cardiac performance. Age-associated alterations of cardiac ECM are therefore able to profoundly affect the function of the conduction system with striking impact on the patient clinical conditions.

The function of the sinoatrial node (SAN) deteriorates with age with an increase in the nodal conduction time and a decrease in the intrinsic heart rate. Collectively, those alterations translate at the clinical side in the so-called sick sinus syndrome, whose manifestations include bradycardia, sinus arrest, and sinus exit block. Additionally, considering the hemodynamic changes occurring with aging, which are basically constituted by a reduction of ventricular compliance and an increased contribution of atrial contraction to ventricular filling, dual chamber pacemakers maintaining synchrony between atria and ventricles are advantageous in older adults. During the aging process, the described structural and functional changes occurring in the left ventricle are interlaced with malfunction of the conduction system, which in turn results in non-efficient and non-synchronous activation of both ventricles, fostering a vicious circle eventually worsening the detrimental effects on cardiac performance.

Conduction disturbances are frequent among the elderly and carry significant morbidity and mortality representing a clinical and economical burden. Complex cellular interplay and paracrine biological signaling underlie this phenomenon and targeting fibrosis generation and its pathological characteristics might be a promising therapeutical approach for age-related arrhythmic disease. Deepening knowledge on ECM age-associated alterations might be important in the development of novel therapeutical approaches in the widespread panorama of age-related disease.

Here is an interesting look at the progression and prevalence of DNA damage leading to leukemia, cancers of bone marrow and white blood cells. Cancer is an age-related disease because its proximate cause is DNA damage and we accumulate ever more of this damage as time goes on. DNA repair systems in our cells and destruction of precancerous cells by the immune system are highly efficient but not perfect, and falter with age due to other forms of accumulating damage. The development of a robust suite of effective cancer treatments is an essential part of progress towards effective treatments for degenerative aging, and perhaps so is a means of DNA repair as well:

It is almost inevitable that we will develop genetic mutations associated with leukaemia as we age. Based on a study of 4,219 people without any evidence of blood cancer, scientists estimate that up to 20 per cent of people aged 50-60 and more than 70 per cent of people over 90 have blood cells with the same gene changes as found in leukaemia. Scientists investigating the earliest stages of cancer development used an exquisitely sensitive sequencing method capable of detecting DNA mutations present in as few as 1.6 per cent of blood cells, to analyse 15 locations in the genome, which are known to be altered in leukaemia. By comparing their findings with other research conducted with a lower degree of sensitivity over whole exomes, the scientists were able to conclude that the incidence of pre-leukaemic cells in the general population is much higher than previously thought and increases dramatically with age.

The pre-leukaemic mutations studied appear to give a growth advantage to the cells carrying them and this starts a process in which cells with these mutations dominate blood making. As they increase in number, the likelihood that one or more of them will acquire more mutations becomes greater, something that could eventually lead to leukaemia and leukaemia-like disorders. Interestingly, the study found that mutations affecting two particular genes, SF3B1 and SRSF2, appeared exclusively in people aged 70, suggesting that these mutations only give a growth benefit later in life, when there is less competition. This finding explains why myelodysplastic syndromes, a group of leukaemia-like conditions associated with these genes, appear almost exclusively in the elderly.

None of the 4219 people studied were found to have a mutation in NPM1, the most common acute leukaemia gene mutated in up to 40 per cent of cases. This unexpected result suggests that mutations in NPM1 behave as gatekeepers for this cancer; once a mutation in this gene occurs in a cell with particular previously accumulated pre-leukaemic mutations, the disease progresses rapidly to become leukaemia. "The significance of mutations in this gene is astonishingly clear from these results: it simply doesn't exist where there is no leukaemia. When it is mutated in the appropriate cell, the floodgates open and leukemia is then very likely to develop. This fits with studies we've conducted in the past in which we found that the gene primes blood stem cells for leukaemic transformation."

Link: http://www.eurekalert.org/pub_releases/2015-02/wtsi-lma022415.php

Researchers are working on a method of delivering cells for cartilage regrowth in aged joints that doesn't use a porous scaffold in order to guide cell growth, but rather relies on the engineering of specific cell characteristics. In theory this should produce a better end result:

In many cases, the cause of age-related joint pain is a loss of hyaline cartilage, which does not have the capacity to regenerate, meaning once gone it is gone forever. Hyaline cartilage is constituted of chondrocytes and its secretions, extracellular matrix (ECM) proteins, which includes collagens II and XI. They do not include collagen I, which is the primary collagen in fibrocartilage, or scar tissue. The key to a successful recovery then is to introduce into the deteriorated cartilage chondrocytes that secrete only hyaline cartilage ECM proteins.

One of the most common strategies for treating hyaline cartilage damage is autologous chondrocyte transplantation. This technique involves acquiring hyaline cartilage from a biopsy and then transplanting it to the injured site. Because the biopsy is smaller than the area that needs repair, the chondrocytes must be expanded, a task that requires enzymatic digestion of the ECM proteins. Unfortunately, the expansion causes the chondrocytes to secrete collagen I, which is why the presence of fibrous tissue is inevitable after such operations.

To solve this problem, researchers report a new protocol that expands not chondrocytes, but induced pluripotent stem (iPS) cells. When a sufficient number of iPS cells are expanded, the protocol then calls for the researchers to differentiate the cells into chondrocytes. Because these chondrocytes are differentiated directly from iPS cells, there is no need to digest ECM proteins, which avoids the problem of fibrous tissue and allows for only hyaline cartilage to be synthesized. Another advantage to this method is that it avoids the use of artificial scaffolds. In other studies artificial scaffolds are included into the transplant to provide support until the chondrocytes begin secreting their own ECM proteins. However, it is unclear if artificial materials prevent optimal integration into the cartilage. Because the chondrocytes have already begun secreting ECM proteins, they can be transplanted without scaffolds.

The team transplanted their particles into three animal models: mouse, rat and mini-pig, finding positive signs for integration and maintenance. "These findings are only preliminary, but they show good indications of safety. The next step is to find the best conditions for transplantation in larger animals before we can consider patient treatment."

Link: http://www.eurekalert.org/pub_releases/2015-02/cfic-sic022315.php

Seeking to recreate the benefits of calorie restriction - greater health and longer life - without the part of the process wherein you must eat less is a grail for modern medical research. The calorie restriction response is of greater benefit to basically healthy people than that produced by any currently available medical technology. Putting forward the idea that people should eat fewer calories is not a popular position in this modern age of comparatively wealth and comfort, however. It is entirely reasonable to expect that any new medicine that safely produced even a sizable fraction of the long term health improvements and slowing of aging triggered by the practice of calorie restriction would make a great deal of money. Thus there is a willingness in the research and development community to invest large amounts in scientific programs that have a chance of making this happen. Based on the pace of progress over the past two decades we shouldn't expect this grail to materialize any time soon, however. Calorie restriction changes near everything that can be measured in the operation of metabolism, and picking apart the complexity of this response costs billions and years even for a tiny slice of progress in understanding. Look at the history of sirtuin research, for example: a lot of hype at the outset, and nothing to show for it today but very expensive knowledge, a tiny addition to a vast catalog yet to be written.

Nonetheless the grail continues to attract attention. To the extent that this draws new funding into human life science research, this is all to the good: there's no such thing as too much life science research. Recreating calorie restriction isn't, however, an effective path to rejuvenation. It's just another way to tinker with the operation of metabolism to gently slow down the damage of aging. This is not particularly helpful to the old, who are already heavily damaged, and if takes decades for the research community to get anywhere, as seems most likely, it is not all that helpful to today's middle aged folk either. Research will always move forward, and tomorrow will be better than today, but it is very important that rejuvenation research aimed at dramatically cutting the rate of death and disease caused by aging moves as rapidly as possible to as beneficial an outcome as possible. Hundreds of millions of lives are the cost of a few years of delay. Calorie restriction mimetic development is a poor, expensive path. We should be focused on repair based strategies like SENS instead, those capable of producing rejuvenation and greatly extended healthy life spans as an outcome.

All things considered practicing calorie restriction now is a great plan. You can do it for next to nothing, and it has an expected beneficial effect considerably larger than any tinkering you can do with supplements and available medical technologies, assuming you're a basically healthy individual. Investing billions and decades and waiting for a drug that can do less for you than eating less? Not such a great plan. Decades and billions should be delivering far better results than that in terms of treatments for degenerative aging.

Here is news of work on a more recent approach to mimicking the effects of calorie restriction: it has become apparent that sensory neurons have a large effect on the calorie restriction response in lower animals, independent of actual calorie intake. This raises the possibility of some form of top-down manipulation in which at least some of the metabolic changes associated with calorie restriction are induced by altering the biochemistry of these sensory neurons. I should note that this is still all very early stage research, however. The grail is really no closer because of it.

Perception of food consumption overrides reality

The study focused on a molecule called AMP-activated protein kinase, or AMPK, which acts as a molecular fuel gauge to detect energy levels. It's been known that AMPK plays important roles in all cell types, but researchers didn't understand which of these activities were most critical to regulating longevity. The researchers found that AMPK inhibited the activity of a protein called CRTC-1 in mitochondria - the primary energy-producing organelles in cells - throughout the organism, by altering production of a neurotransmitter.

The researchers were struck by the fact that altering the AMPK pathway in just a limited set of neurons was sufficient to override its effects on metabolism and longevity in other tissues. Aging was influenced more by what the animals perceived they were eating than what they actually ate. The study suggests that manipulating this energy-sensing pathway can cause organisms to perceive their cells to be in a low-energy state, even if they are eating normally and energy levels are high. Drugs targeting the cells' energy-sensors in this way could potentially address age-related diseases, including cancer and neurodegeneration, and may offer an alternative to calorie restriction.

Neuronal CRTC-1 Governs Systemic Mitochondrial Metabolism and Lifespan via a Catecholamine Signal

Low energy states delay aging in multiple species, yet mechanisms coordinating energetics and longevity across tissues remain poorly defined. The conserved energy sensor AMP-activated protein kinase (AMPK) and its corresponding phosphatase calcineurin modulate longevity via the CREB regulated transcriptional coactivator (CRTC)-1 in C. elegans. We show that CRTC-1 specifically uncouples AMPK/calcineurin-mediated effects on lifespan from pleiotropic side effects by reprogramming mitochondrial and metabolic function. This pro-longevity metabolic state is regulated cell nonautonomously by CRTC-1 in the nervous system. Targeting central perception of energetic state is therefore a potential strategy to promote healthy aging.

When it comes to the mechanisms by which the operation of metabolism determines natural variations in longevity, few areas are as well studied as the role of insulin and insulin-like growth factor (IGF-1). This is no doubt in part due to the size and influence of the type 2 diabetes research community, but it is also the case that most of the methods so far demonstrated to slow aging and extend life in mice, such as calorie restriction, appear to act at least partially through alterations to insulin metabolism and related systems. Here is a review on this topic, with a focus on the brain:

Insulin is the most powerful anabolic hormone discovered to date. Besides the well-established action of insulin in peripheral organs, such as liver, muscle, and adipose tissue, it is becoming increasingly clear that insulin affects important features of glucose metabolism via central mechanisms. Insulin signaling has been linked to longevity in organisms ranging from nematodes to mammals.

There is an impressive body of literature implicating insulin/IGF-1 like ligands and insulin/IGF-1 signaling in the regulation of metabolism, development, and longevity in the roundworm C. elegans. In response to food or the perception of food, multiple insulin-like ligands are secreted from neurosecretory cells in the brain of C. elegans and D. melanogaster, indicating that in these invertebrates, the central nervous system (CNS) plays a key role in insulin signaling mediated regulation of physiology and lifespan in response to environmental cues. In mammals, the insulin/insulin-like growth factor-1 signaling cascade exhibits some striking differences compared to the insulin/insulin-like growth factor-1 signaling cascade in invertebrates. These differences include the acquisition of growth hormone as a main regulator of IGF-1 production by the liver, and the acquisition of separate receptors for insulin and IGF-1. Again, several of the existing long-lived mammalian mutants with defects in insulin/IGF-1 signaling point to a role of the CNS in the regulation of mammalian longevity.

Also in humans, preserved insulin sensitivity has been associated with longevity. Insulin resistance has been shown to predict the development of age-related diseases, including hypertension, coronary heart disease, stroke, cancer, and type 2 diabetes. In the general population, the association between aging and decline in insulin sensitivity has been demonstrated in several studies. Mechanisms suggested to contribute to decreased insulin sensitivity in the elderly include (i) age-related receptor and post-receptor defects in insulin action, (ii) an age-related decrease in insulin stimulated whole body glucose oxidation, (iii) an age-related reduction in beta cell response to glucose, and (iv) impaired insulin-mediated glucose uptake, and inability to suppress hepatic glucose output. In contrast, centenarians, which exhibit exceptional longevity, seem protected against the age-related decline in insulin sensitivity when compared to a group of advanced middle-aged individuals.

We speculate that healthy longevity is associated with preserved brain insulin action. Enhanced insulin efficacy might occur through measures aimed at minimizing inflammation; and enhanced delivery might be promoted to the brain areas that are crucial for healthy longevity. Inflammation, including that occurring in the hypothalamus, has been linked to age-related decline in insulin sensitivity. Physical exercise is known to be protective against numerous diseases and reduction of inflammation has been implicated in the health benefits conferred by exercise. Notably, a lower intake of calories and food that is rich in saturated fat and carbohydrates has been shown to reduce inflammaging. Future research may focus on hypothalamic microglia as relevant targets for prevention and treatment of metabolic disorders.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4319489/

There are a score or so of different forms of amyloid that accumulate in the aging body and brain. These are misfolded proteins that precipitate out of tissue fluids to form clumps, and the biochemistry surrounding this process can cause harm in numerous ways. Alzheimer's disease is associated with amyloid-beta, and long years of research in that field illustrate that the mechanisms by which amyloid formation can damage tissue function are potentially very complex. A few other forms of amyloid are directly linked to age-related disease, but many are not, or ambiguity remains regarding how they are harmful. Still, the presence of amyloid is a clear difference between young tissue and old tissue. Any potential rejuvenation toolkit should include a way to safely clear these misfolded protein aggregates, such as via immunotherapies of the sort under development as potential Alzheimer's treatments.

Here is a speculative paper on the role of microbes in amyloid accumulation in the body. While reading note that amyloid levels, at least for amyloid-beta, are very dynamic. The body can clear it, but those clearance processes either diminish with the damage of aging or are slowly overwhelmed by increased generation:

Atypical amyloid generation, folding, aggregation and impaired clearance are characteristic pathological features of human neurodegenerative disorders including Alzheimer's disease (AD). What is generally not appreciated is that a major secretory product of microbes is amyloid, and that the contribution of microbial amyloid to the pathophysiology of the human central nervous system (CNS) is potentially substantial. While earlier findings suggested that these amyloids may serve some immune-evasive strategy, it has recently become evident that humans have a tremendously heavy systemic burden of amyloid which may contribute to the pathology of progressive neurological diseases with an amyloidogenic component.

Diverse microbes of the human microbiome generate functional amyloids. The large amount of microbial-generated GI amyloid implicates high potential systemic exposure to bacterial amyloid, and the bioavailability of amyloid to the CNS increases as humans age. Microbial and CNS amyloids are biologically similar in their structure and immunogenicity and complex mechanistic interrelationships between these amyloids are beginning to emerge.

Microbes or their secretory or degradation products including their amyloids and lipopolysaccharides are powerful inflammatory activators and inducers of cytokines and complement proteins, affecting vascular permeability and generating free-radicals that further support amyloidogenesis. These pathogenic signaling features are also highly characteristic of AD neuropathology. A more detailed understanding of human microbial ecosystems and their amyloids should give insight into amyloid-misfolding and their contribution to inflammatory-signaling in health, aging and disease. It will certainly be interesting to see: (i) if any microbial-generated amyloids co-localize with the amyloid-dense senile plaque deposits of AD; (ii) if GI tract microbiome-derived amyloids become more available systemically as humans age; and (iii) what the evolution and nature of amyloid-related communication between the gastrointestinal tract and the CNS has on the development or propagation of amyloids in pro-inflammatory degenerative disease.

Link: http://dx.doi.org/10.3389/fnagi.2015.00009

Ours is an era on the verge of developing means to treat the root causes of degenerative aging and thereby extend healthy life, eliminate age-related disease, and rejuvenate the old. The decades ahead are a critical time, in which the best and most promising approaches to research and development either take off or falter. There are all too many examples from the past in which promising new technologies languished long past the point at which they could have been created and made widely available. We don't want that to happen here, as it means the difference between health or frailty, life or death for all of us.

The first in a series of Rejuvenation Biotechnology conferences organized by the SENS Research Foundation was held late last year, and by all accounts went very well. You should certainly take a look at the BioWatch News special issue devoted to the conference and its goals if you have not already done so. It is a thoughtful look at some of the issues facing research and development in those parts of the field of aging research focused on intervention and cures.

The aim of the Rejuvenation Biotechnology conference series is to lay the groundwork for closer collaboration between industry and research establishments in the development of near future therapies to treat degenerative aging. The scientific foundations needed for rejuvenation therapies are progressing at a pace that is far slower than we'd all like, but it is nonetheless time to prepare the way for clinical translation of research results. That process takes time, and to pick one example, initial attempts at clearance of senescent cells might be only a few years away from initial clinical trials at this point: a for-profit startup company was recently founded to work on one approach. While it is easy to imagine that any practical treatment for aging would be mobbed by developers seeking to bring it to market as soon as it makes it out of early stage research, in truth that sort of outcome only happens when sufficient preparation has taken place. That means at the very minimum building a network of relationships and knowledge.

Videos of presentations given at the Rejuvenation Biotechnology conference were recently posted by the SENS Research Foundation staff. I think you'll find them interesting. Many more than are shown here can be found at the SENS Research Foundation YouTube channel.

The Rejuvenation of Aged Skeletal Muscle by Systematic Factors

The primary research focus of the Jang laboratory is to understand the molecular and biochemical mechanisms of age-related muscle loss and function. The Jang laboratory applies bioengineering approaches and stem cell-based therapies to study skeletal muscle dysfunction during aging and in age-associated muscle diseases. The laboratory develops and applies novel tools using a combination of animal and stem cell models.

A Twist of Fate - Generating New Neocortical Neurons

The line of investigation aims to establish ways of regenerating the principle neurons of the adult cerebral cortex when these neurons are lost due to trauma or degeneration, including degeneration due to aging. Since endogenous precursors do not replace cortical neurons when they are lost, two strategies are being developed: manipulating these precursors with molecular genetic techniques to start generating neurons and transplanting engineered precursors that are programmed to disperse in the cortex and differentiate into cortical projection neurons.

Building a Rejuvenation Biotechnology Industry - Panel Discussion

This panel synthesized the discussions from all of the conference sessions and panels. A cross-section of academics, pharmaceutical reps, policy makers, and other presenters revisited the merits of a damage repair paradigm to address the diseases of aging considered at this conference. Panelists considered the changes that would be required to lay the groundwork for a new industry perspective focused on addressing damage indications for the diseases of aging either through preventing or repairing such damage.

Via the Buck Institute Science of Aging blog, here is a look at the work of a scientist who specializes in the intersection of the stem cell and aging fields, an area that includes cancer and regenerative research:

Hematopoietic stem cells regenerate over a person's lifetime and can differentiate into all the different blood cell types found in humans, such as T-cells and B-cells. In principal, the hematopoietic stem cell population can regenerate from a single cell. So in theory a single transplanted cell can repopulate the pool. We have tried to do this in the hematopoietic system of old mice by taking hematopoietic stem cells from young mice and transplanting them into old mice, and the result was disappointing. The new stem cells did not integrate well and the aged in vivo environment did not allow for the newly introduced stem cells to function properly. In terms of using induced pluripotent stem cells (IPS cell) there are additional risks involved. IPS cells can transform and become cancerous, and they need to be generated and differentiated in culture, which is both time consuming and costly. I think trying to better understand why endogenous stem cells stop functioning and then adjusting the environment in vivo to keep them active, is a promising alternative avenue of treatment.

Studies have shown that stem cells are often the origin of many cancers. Due to their long lives and high replication rate, when compared to somatic cells, stem cells have an increased risk of acquiring DNA mutations that can cause cancer and other diseases. When studying hematopoietic stem cells, it is possible to isolate them from a simple blood sample. These cells can then have their DNA sequenced for possible mutations that might lead to cancer. With a better understanding of these mutations, new cancer treatments that are genetically designed and targeted for those mutations can be created, and then used in a patient specific manner. The problem is that although you may be able to test for these predictive mutations in other tissues, it is very difficult to obtain tissue samples from various organs. One must also keep in mind that a mutation detected in blood cells is not always present in other organs. The mutations that we are detecting are not always those that one is born with but also those that occur over a person's lifetime due to continual DNA damage and repair. So different cells and organs will have different mutations that occur over time. People are now developing nanotechnologies to take measurements from different cells.

Link: http://sage.buckinstitute.org/interview-with-dr-karl-lenhard-rudolph-mechanisms-of-aging-and-transformation-of-stem-cells/

Tissue engineering of muscle continues to move forward, with a new approach here demonstrated in mice:

Tissue engineering of skeletal muscle is a significant challenge but has considerable potential for the treatment of the various types of irreversible damage to muscle that occur in diseases like Duchenne muscular dystrophy. So far, attempts to re-create a functional muscle either outside or directly inside the body have been unsuccessful. In vitro-generated artificial muscles normally do not survive the transfer in vivo because the host does not create the necessary nerves and blood vessels that would support the muscle's considerable requirements for oxygen. Now, however, researchers have succeeded in generating mature, functional skeletal muscles in mice using a new approach for tissue engineering. The scientists grew a leg muscle starting from engineered cells cultured in a dish to produce a graft. The subsequent graft was implanted close to a normal, contracting skeletal muscle where the new muscle was nurtured and grown.

The scientists used muscle precursor cells - mesoangioblasts - grown in the presence of a hydrogel (support matrix) in a tissue culture dish. The cells were also genetically modified to produce a growth factor that stimulates blood vessel and nerve growth from the host. Cells engineered in this way express a protein growth factor that attracts other essential cells that give rise to the blood vessels and nerves of the host, contributing to the survival and maturation of newly formed muscle fibres. After the graft was implanted onto the surface of the skeletal muscle underneath the skin of the mouse, mature muscle fibres formed a complete and functional muscle within several weeks. Replacing a damaged muscle with the graft also resulted in a functional artificial muscle very similar to a normal tibialis anterior.

Link: http://www.alphagalileo.org/ViewItem.aspx?ItemId=150064&CultureCode=en

There are now many lineages of genetically engineered mice that exhibit longer healthy, median, and maximum life spans, though none have yet come close to the 60-70% record set by growth hormone loss of function mutants. It is no longer newsworthy for a new variety of long-lived mouse to be discovered, and indeed many now pass by without comment. Extending life in mice by 10-30% through a single genetic alteration is a commonplace occurrence. Many of these interventions work through an overlapping set of related mechanisms that can be manipulated at many points, such as increased cellular housekeeping, and many are related to the calorie restriction response, the increase in health and life span that occurs due to a lower calorie intake.

Slowing aging by altering the operation of metabolism is ultimately not the real path to extending human life spans. Firstly where we can make direct comparisons between results in short-lived animals and results in humans, the effects on human life span are minimal even when the short term health benefits are similar. Calorie restriction certainly doesn't extend life by 40% in humans as it can in mice. Growth hormone loss of function mutations in humans such as Laron syndrome do not produce people who live vastly longer than the rest of us. Secondly a way slow aging will not help old people: what good is it to slow down the rate of damage accumulation for someone already so damaged as to be close to death? We want damage repair, means of rejuvenation, not mere slowing of the decline. Thirdly it is proving to be enormously expensive to make any real progress on this front: billions of dollars over two decades has produced only knowledge, and no practical treatment that comes anywhere near the proven benefits provided by regular moderate exercise or calorie restriction.

Slowing aging is a great way to investigate the vast unknown areas of cellular metabolism if the end goal is only knowledge, producing the catalog of human metabolism down to the tiniest detail, and not a matter of extending human life span. If we want longer lives, then the research community should be focused on rejuvenation through damage repair, which is a completely different research strategy in comparison to slowing aging. The aim is not to alter the operation of metabolism at all, but instead to periodically sweep away the damage that occurs as a side-effect of its normal operation.

This is not to say that research into slow-aging mutants is uninteresting. On the contrary, it is exciting stuff if you like to follow progress in the life sciences. A great deal is being learned and scarcely a day goes by without something newsworthy turning up. For example there is this open access paper, in which a calorie-restriction-like method of extending life is shown to improve wound healing in old age. Note that this lineage of long-lived mice (exhibiting a 20% increase in life span or thereabouts) was not created for that purpose, and has existed for more than 20 years. The canonical review paper on their longevity is from 1999. It is entirely possible that there are as yet a range of mouse lineages in labs that exhibit modest life extension and yet no-one has noticed because life span studies haven't been carried out:

Wound healing and longevity: Lessons from long-lived αMUPA mice

Although there is no clear consensus on whether aging affects the quality of skin wound healing (SWH), the rate of SWH is often used as one of the biomarkers for biological age and could be indicative of a longevity phenotype. However, a clear-cut answer as to whether the longevity phenotype is associated with accelerated SWH remains obscure. Even in case of calorie restriction (CR), one of the most successful longevity-promoting interventions in mammals, the few studies conducted thus far did not bring about decisive results.

To address this issue, we investigated SWH in the long-lived transgenic αMUPA mice, a unique genetic model of extended lifespan. The αMUPA mice carry a transgene specifically expressed in the ocular lens. Being initially generated in 1987 to investigate eye pathologies, these transgenic mice were unexpectedly found to display a longevity phenotype. Compared to their wild type (WT) counterparts, the αMUPA mice spontaneously eat less when fed ad libitum, and live longer. The αMUPA mice also maintain an overall young look and physical activity at advanced ages and show a significantly reduced rate of spontaneous and induced tumorigenesis. Thus, the αMUPA mice share many common features with CR, yet are not hindered by several major drawbacks of CR such as hunger-induced stress and a need for individual housing (social stress). In view of using αMUPA mice as a CR-mimicking model to study the impact of CR on SWH, it is important to stress that the αMUPA mice strongly express the transgene in the ocular lens and ectopically in the brain but not in the skin, thus excluding the gene-specific effects on SWH.

We found that αMUPA mice showed a much slower age-related decline in the rate of WH than their wild-type counterparts. After full closure of the wound, gene expression in the skin of old αMUPA mice returned close to basal levels. In contrast, old wild-type mice still exhibited significant upregulation of genes associated with growth-promoting pathways, apoptosis and cell-cell/cell-extra cellular matrix interaction, indicating an ongoing tissue remodeling or an inability to properly shut down the repair process. It appears that the CR-like longevity phenotype is associated with more balanced and efficient WH mechanisms in old age, which could ensure a long-term survival advantage.