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Nonetheless, researchers are now investigating a range of natural compounds and their derivatives that have been claimed to affect aging in mice, even to only very small degrees, and curcumin and its analogs are in that list. This is one of many programs
of dubious utility that obtain far too much funding and interest in comparison to the benefits they might plausibly delivery. My suspicion is that this will turn out to be an exercise of largely academic interest, better categorizing a range of marginal
ways to influence aging, but until such time as fisetin is rigorously tested in humans, there is always that to point to as a counterargument. Further, since it is much cheaper to develop natural compounds, there will always be those who choose to fish
in the shallows just because it is easier to fish in the shallows, regardless of the fact that the rewarding catches are only found further out. This is exactly why we have more research into curcumin than into many of the branches of SENS rejuvenation
research. It is a waste in the grand scheme of things, a distraction, but it will nonetheless occupy a great deal of time and resources.

The curcumin analog EF24 is a novel senolytic agent

The mechanisms by which senescent cells (SCs) accumulate with aging have not been fully understood but may be attributable in part to immune senescence that decreases the ability of the body to clear SCs. Although cellular senescence is a tumor-
suppressive mechanism, SCs can play a causative role in aging and age-related diseases when they accumulate. This suggestion is supported by the finding that genetic elimination of SCs in naturally aged mice through a transgene can delay various age-
dependent deterioration in tissues and organs and extend their lifespan.

This seminal finding stimulates research to identify small molecules termed senolytic agents that can selectively kill SCs as potential therapeutics for age-related diseases. To date, several classes of senolytic agents have been identified, and most of
them are natural compounds such as quercetin, fisetin, and piperlongumine. Because natural senolytic compounds have the advantages of low toxicity, they may have a better chance to be translated into clinic to treat age-related diseases or can be used as
a lead for the development of more specific and potent senolytic agents.

Curcumin, a natural compound extracted from turmeric, has a broad range of biological and pharmacological activities, including antioxidant, anti-inflammatory, antimicrobial, and anti-cancer activities. Numerous studies suggest that curcumin has some
health benefits in delaying aging and may be useful in preventing and treating age-related diseases. For example, curcumin was shown to prolong lifespan and extend healthspan in Drosophila melanogaster and Caenorhabditis elegans. To improve the
bioavailability and biological activity of curcumin, many curcumin analogs were developed, including EF24, HO-3867, 2-HBA, and dimethoxycurcumin, which have been demonstrated to be more active than curcumin in preventing and treating various diseases and
reducing age-dependent deterioration. However, the mechanisms of their anti-aging action have not been fully elucidated.

We hypothesized that curcumin and its analogs may increase healthspan in part by functioning as novel senolytic agents. Therefore, in this study, we examined the senolytic activity of several curcumin analogs and found that EF24 is a novel potent and
broad-spectrum senolytic agent in cell culture. We show that EF24 can selectively reduce the viability of human SCs from different tissue origins and induced by different stresses. Its senolytic effect is likely attributable to the induction of apoptosis
via proteasome-mediated downregulation of the Bcl-2 anti-apoptotic family proteins such as Bcl-xl. These findings provide new insights into the mechanisms by which curcumin and its analogs function as anti-aging agents and suggest that the curcumin
analog EF24 has the potential to be used as a novel senolytic agent for the treatment of age-related diseases.

PU.1 Inhibition as a Potential Therapy to Suppress Fibrosis https://www.fightaging.org/archives/2019/02/pu-1-inhibition-as-a-potential-therapy-to-suppress-fibrosis/

Researchers here suggest that PU.1 is a master regulator of fibrosis, and thus inhibition could be an effective treatment for the various fibrotic diseases that presently lack good options for patients. Fibrosis is a dsyregulation of the normal processes
of tissue maintenance, in which scar-like deposits of collagen are formed, disrupting tissue structure and function. When this progresses far enough, it is ultimately fatal: consider the fibrotic diseases of heart, lungs, and kidney, for example. There
is evidence for the presence of senescent cells to contribute to fibrotic diseases. Given this new information about PU.1 it, it will be interesting to see if the mechanisms by which scarring forms can be traced back to specific signaling on the part of
senescent cells, and thus further reinforce senolytics as a therapy for fibrosis.

In connective tissue diseases such as systemic sclerosis, referred to collectively as 'fibrosis', excessive activation of connective tissue cells leads to hardening of the tissue and scarring within the affected organ. In principle, these diseases can
affect any organ system and very often lead to disruption of organ function. Connective tissue cells play a key role in normal wound healing in healthy individuals. However, if the activation of connective tissue cells cannot be switched off, fibrotic
diseases occur, in which an enormous amount of matrix is deposited in the tissue, leading to scarring and dysfunction of the affected tissue. Until now, scientists did not fully understand why repair processes malfunction in fibrotic diseases.

Researchers now been able to decipher a molecular mechanism responsible for the ongoing activation of connective tissue cells. In experimental studies, the researchers targeted the protein PU.1. In normal wound healing, the formation of PU.1 is inhibited
by the body so that at the end of the normal healing process the connective tissue cells can return to a resting state. "We were able to show that PU.1 is activated in various connective tissue diseases in the skin, lungs, liver and kidneys. PU.1 binds
to the DNA in the connective tissue cells and reprograms them, resulting in a prolonged deposition of tissue components."

PU.1 is not the only factor involved in fibrosis, as factors that are involved in the deposition of scar tissue have already been identified in the past. What has been discovered now, however, is that PU.1 plays a central role in a network of factors
controlling this process. "PU.1 is like the conductor in an orchestra. If you take it out, the entire concert collapses." This approach has already been tested using an experimental drug, fuelling the hope that clinical trials on inhibiting PU.1 may soon
be able to be launched, aimed at better treating fibrosis.

Arguing for Exercise to be a Useful Treatment for Sarcopenia Because it Affects Mitochondria, Unlike Most Other Attempted Interventions
https://www.fightaging.org/archives/2019/02/arguing-for-exercise-to-be-a-useful-treatment-for-sarcopenia-because-it-affects-mitochondria-unlike-most-other-attempted-interventions/

In this open access paper, the authors argue that exercise (and particularly strength training) remains the best therapy for sarcopenia, the age-related loss of muscle mass and strength, because exercise improves mitochondrial function and other
attempted treatments do not. This seems a reasonable position. There are many, many possible contributing causes of sarcopenia, all with accompanying evidence, but the most compelling in my opinion is stem cell dysfunction. Even so, one still needs to
offer an explanation as to why exactly stem cell activity in muscle tissue declines with age, a way to link it to the root cause molecular damage of aging listed in the SENS research proposals. Perhaps faltering mitochondrial function is a noteworthy
underlying cause.

Resistance exercise continues to be the most effective intervention against sarcopenia. In addition, maintenance of physical activity can delay the progression of sarcopenia. Despite the strong support for maintaining an active lifestyle, adherence to
physical activity guidelines remains low. The traditional therapeutic focus of sarcopenia treatment is to target growth-related pathways to increase muscle mass. Here, we discuss the positives of these strategies, but also build a case for targeting
mitochondrial bioenergetics as a way to maintain muscle mass and function with age.

The vast majority of adults fail to meet physical activity guidelines. While 60% of adults, both European and American, self-report that they meet guidelines, objectively measured physical activity reveals that fewer than 10% of adults in the United
States meet physical activity guidelines. Moreover, sedentary behavior alone increases the risk for sarcopenia. While there are few trials in humans on the effects of lifelong sedentary behavior, studies in mice reveal lifelong sedentary behavior impairs
mitochondrial function.

It was thought that resistance exercise training had little or no effect on mitochondrial biogenesis or function. However, recent studies have shown that resistance exercise training increases mitochondrial protein fractional synthesis rates (FSRs) and
improves mitochondrial function. Young adults engaged in a resistance exercise program showed increases in mitochondrial enzyme activity and respiration. While the changes in mitochondrial respiration are modest in comparison to endurance exercise,
improvements in in vivo phosphocreatine recovery rates and oxidative capacity appear comparable in older adults engaged in either exercise intervention.

Aerobic exercise is generally not appreciated as a stimulator of hypertrophy; however, there is evidence that it can lead to muscle hypertrophy. Nearly half a century ago, it was first documented that aerobic exercise increases mitochondrial content.
Since then, research has consistently documented that aerobic exercise improves both mitochondrial content and function. Aerobic exercise increases mitochondrial turnover since it increases both mitochondrial biogenesis (protein synthesis) and mitophagy (
mitochondrial-specific autophagy). The improvement in the rate of ATP production from aerobic exercise training suggests that more energy is available to maintain proteostasis. Additionally, improvement in mitochondrial efficiency (reduction in ROS
generated per oxygen consumed or ATP generated) suggests that there is less oxidative stress and damage, which would in turn improve the quality of the proteome. In all, aerobic exercise mediated improvements in mitochondrial function likely protects
against sarcopenia.

Delivery of Senolytics Can Help Following Acute Kidney Injury, but Tissue Damage and Loss of Function Remains
https://www.fightaging.org/archives/2019/02/delivery-of-senolytics-can-help-following-acute-kidney-injury-but-tissue-damage-and-loss-of-function-remains/

Researchers here investigate the mechanisms by which senescent cells are created during acute kidney injury (AKI). Senescent cells are usually created as a part of the injury and regeneration process, and then destroyed quickly afterwards, but there is
more to it in this case. The senescent cells linger and their signaling causes fibrosis, a form of scarring that further harms the injured kidney. The researchers find that some (but not all) senolytic drugs can clear out these senescent cells, reducing
fibrosis. However, introducing this treatment after AKI failed to lead to regeneration of damage to the tubule structures of the kidney. That only some senolytics work for this particular type of senescent cell and tissue is perhaps the most interesting
finding here: it reinforces the developing thesis that there are significant differences between senescent cells in different tissues and circumstances, and thus variety is desirable in the development programs for small molecule senolytic drugs.

Tubule repair is a common event after kidney injury, but is frequently associated with interstitial inflammation and maladaptive processes that lead to fibrosis, the hallmark of all forms of kidney disease and a reliable predictor of progression to
chronic kidney disease(CKD). Recently, multiple studies identified multipotent mesenchymal stromal progenitor cells (pericytes) as the cell population that is responsible for collagen deposition after injury. Kidney fibrosis has also been correlated with
arrest of tubular epithelial cells (TECs), which suggests that the epithelium plays a primary role in the progression of kidney disease. However, the factors that contribute to the cell cycle arrest are not known. Cell cycle arrest is a universal marker
of cellular senescence and is evoked by a variety of stressors.

Several studies have reported a correlation between the presence of senescent cells and kidney fibrosis both during the aging process and in the context of disease, but a systematic study of cellular senescence after AKI and its potential contribution to
the progression of tubular damage and fibrosis is lacking. Here, we show that in mice TECs commonly become senescent after various types of kidney injury, and that this occurs surprisingly early after injury. We show that senescent TECs express higher
levels of proinflammatory factors of the SASP as a result of cell-autonomous control by the TLR/IL-1R-mediated innate immune signaling pathway, and that senescent TECs are a source of the mesenchymal progenitor-activating ligands.

Tubule-specific inhibition of TLR/IL-1R signaling by conditional inactivation of the Myd88 gene prior to senescence not only reduced the levels of epithelial cell-derived proinflammatory cytokines, interstitial infiltration, and fibrosis, but also
decreased the accumulation of senescent cells and ameliorated tubular damage. Whereas inactivation soon after injury was equally effective in decreasing the number of senescent TECs, inflammation, and fibrosis, it did not protect from tubular damage.
Similarly, eliminating p16+ senescent cells, but not senescent cells by FOXO4-DRI inhibitory peptide, which induces apoptosis of senescent cells by disrupting the interaction between FOXO4 and p53, reduced kidney fibrosis without reducing tubular damage.

Our results indicate that TEC senescence is a common and early event after kidney injury, and that signaling by the TLR/IL-1R pathway within the epithelium controls this phenomenon. Our findings also suggest that early intervention after injury is likely
required to reduce organ damage after AKI. Furthermore, this study reveals what we believe is a novel function of the epithelial TLR/IL-R1 signaling in controlling the onset of TEC senescence in a cell-autonomous manner, consistent with the concept that
the tubular epithelium triggers kidney disease following injury and also drives its progression.

Arguing that Public Desire for Greater Longevity is Growing https://www.fightaging.org/archives/2019/02/arguing-that-public-desire-for-greater-longevity-is-growing/

Our community has undertaken years of advocacy for rejuvenation research, with the aim of developing ways to reverse age-related disease and disability, and thus greatly extend healthy life spans. The first concrete results are emerging from the research
community, the result of philanthropy and persuasion, then the incremental accretion of funding to programs that showed promising initial data. So now we have senolytics, and I would hope not too many years from now we'll have glucosepane cross-link
breakers - and then more thereafter.

But have we persuaded the broader public at all? Have we convinced more than a small number of people of the plausibility of the goal of human rejuvenation? Of the merits of ending aging, of eliminating the enormous scope of suffering and death that is
all around us? At the large scale, and over decades, progress requires public support. Aging research as a whole needs the same widespread, overwhelming support enjoyed by HIV or cancer research programs; the history of both of those vast patient
advocacy initiatives is well worth studying. We are not there yet. But are we further along than was the case at the turn of the century? You might compare the results of the survey noted here with another survey conducted last year; while it certainly
looks like progress, I think it is far from clear as to where exactly things stand.

People generally do not believe in the plausibility of targeting the mechanisms of aging in order to slow down and reverse age-related damage. After so many millennia of fruitless dreams, with so many powerful psychological defenses that protect our
state of mind when we face the idea of inevitable death by aging, becoming hopeful is usually too much to ask. This can explain why most people, when asked about their desired lifespan, add only a few years to the life expectancy of their given countries.

However, in the last few years, things have apparently started to change. In 2015, in a study by Donner et al, it was found that given perfect mental and physical health, 797 out of 1000 participants wanted to live to 120 or longer; over half of these
797 people desired unlimited lifespans (around 40% of all participants). A new study by YouGov shows even more impressive results. We at Lifespan.io generally stay away from strong statements such as "living forever" or "immortality", because these
expressions are hardly scientific and have a religious background. The notion of immortality even seems to scare some people because it seems to limit their freedom and because immortals are pictured by pop culture as criminals, crazy, or morally
inferior. Therefore, people often reject the idea of extended life without perfect health.

However, in a new study by YouGov that included around 1200 participants, one in five (19%) people agreed with the statement "I want to live forever" without any promises related to perfect health. 42% of the participants chose "I want to live longer
than a normal lifespan, but not forever", while 23% said, "I don't want to live longer than a normal lifespan." People in different age groups reacted to this survey differently; it turns out that the idea of radical life extension was more supported by
young people (24%) than by people over 55 (13%), while support for the status quo was the opposite (19% of young people didn't want to live longer than a normal lifespan, while this position was shared by 29% of people aged 55 and older).

The YouGov survey participants were randomly selected, and few of them will be regularly exposed to news about aging and longevity research. However, over 60% explicitly expressed a desire for radical life extension. That is a big jump from the Pew
Research study from 2013, where only 38% of the participants expressed the desire to undergo medical treatments to slow aging and live to be 120 or more. Of course, the questions in these surveys were formulated differently, so we cannot directly compare
them. However, looking at various, similar studies, it appears that, in the last 5 years, 20% more Americans have become aware that something serious is going on in the rejuvenation biotechnology industry.

Age-Related Diseases are Just the Names we Give to Portions of Aging https://www.fightaging.org/archives/2019/02/age-related-diseases-are-just-the-names-we-give-to-portions-of-aging/

Aging is a process of damage accumulation in cells and tissue structures, followed by reactions to that damage, some of which are compensatory and some of which make matters worse, and lastly the consequent failure of biological systems necessary to
support health and life. Age-related diseases are names we give to some of the aspects of system failure, but they are not distinct from aging. One cannot draw a line between aging and age-related disease; it is a futile endeavor, and that the medical
industry and regulatory bodies are set up to do so is one of the major challenges facing those who want to develop commercial rejuvenation therapies based on clearance of senescent cells or other recent scientific advances.

This point about aging and age-related disease is somewhat reinforced by the genetic analysis noted here, though I'm yet to be convinced of the utility of this sort of research beyond gaining a purely curiosity-driven scientific understanding of how
aging progresses in detail. Since we all age for the same reasons, the same underlying damage, and since rejuvenation therapies will repair that damage in the same way in all patients, and since we have a good list of that damage, there are certainly
days when it seems to me that anything other than just building the repair therapies and testing their effects is something of a sideline.

"According to Gompertz mortality law, the risk of death from all causes increases exponentially after the age of 40 and doubles approximately every 8 years. By analyzing the dynamics of disease incidence in the clinical data available from the UK Biobank,
we observed that the risks of age-related diseases grow exponentially with age and double at a rate compatible with the Gompertz mortality law. This close relation between the most prevalent chronic diseases and mortality suggests that their risks could
be driven by the same process, that is aging. This is why healthspan can be used as a natural proxy for investigation of the genetic factors controlling the rate of aging, the 'holy grail' target for anti-aging interventions."

To find genetic factors associated with human healthspan, the researchers studied the genomes of 300,477 British individuals. Overall, 12 genetic loci affecting healthy life expectancy were discovered. To confirm that these results hold true for other
ethnicities, they used genetic data of UK Biobank participants with self-reported European, African, South Asian, Chinese and Caribbean ancestry. Of the 12 single nucleotide polymorphisms (SNPs), 11 increased risk both in discovery and in replication
groups. Three of the genes affecting healthspan, HLA-DQB, LPA, and CDKN2B, were previously associated with parental longevity, a proxy for overall life expectancy.

At least three genetic loci were associated with risk of multiple diseases and healthspan at the same time and therefore could form the genetic signature of aging. HLA-DQB1 was significantly associated with COPD, diabetes, cancer, and dementia in this
study and was demonstrated to be associated with parental survival earlier. The genetic variants near TYR predict death in the prospective UKB cohort and are involved in the earlier onset of macular degeneration. The chromosome 20 locus containing
C20orf112 was not associated with the incidence of any of the diseases at the full-genome level, and yet was affecting the healthspan of studied individuals.

Calorie Restriction Reduces Neuroinflammation https://www.fightaging.org/archives/2019/02/calorie-restriction-reduces-neuroinflammation/

Calorie restriction, also known as dietary restriction in the scientific community, is the practice of consuming up to 40% fewer calories than usual, while still obtaining optimal levels of micronutrients. It produces sweeping changes in the operation of
cellular metabolism, slows near all measures of aging, and extends life in mice. Thus for any particular aspect of aging, and here the focus is on chronic inflammation in the brain that accelerates progression of age-related neurodegeneration, it is
possible to invest a great deal of time and effort into investigating just how calorie restriction slows it down.

This sort of work is of great scientific interest, as it will help researchers to build a comprehensive map of cellular metabolism and the changes that take place over the course of aging. It is not, however, a road to rejuvenation. Calorie restriction,
like all approaches involving upregulation of cellular stress responses, has a much smaller effect on life span in humans than in short-lived species such as mice. There isn't a way to conjure a reversal of aging in the elderly from this biochemistry.
That requires a completely different strategy, based on identification of root cause damage, and repair of that damage, as outlined in the SENS roadmap for development of rejuvenation therapies.

A growing body of evidence demonstrates that dietary restriction (DR) exerts its beneficial effects on brain aging at multiple levels. Although there is some degree of discrepancy across studies, likely due to the difference in the model organisms and
experimental design, DR appears to mitigate all of the morphological and functional alterations in the brain associated with aging. A major hallmark of aging is systemic, low-grade chronic inflammation throughout the body, termed inflammaging. Notably,
these inflammatory signs are similar to the ones associated with obesity and metabolic diseases, providing a possible glimpse into why DR exerts anti-inflammatory effects on aging-associated inflammation.

As with other organs, chronic low-grade inflammation is a common feature of the aged brain. Neuroinflammation is a host defense mechanism against harmful stimuli and damage in the brain. However, chronic inflammation can be deleterious in normal aging as
well as in pathological aging related to neurodegenerative diseases. The central nervous system (CNS) is composed of heterogeneous cell types, including neurons, microglia, astrocytes, and oligodendrocytes. Although two major glial cell types, astrocytes
and microglia, are known to be key players in inflammatory responses in the brain, it is now well recognized that all neural cells participate to some degree in the neuroinflammatory responses.

Neuroinflammation often manifests as astrogliosis, microgliosis, and an increase in secreted inflammatory mediators, such as cytokines, chemokines, and complement proteins. Accumulating evidence from clinical and basic research suggests that
neuroinflammation is tightly connected to the decline in brain function during aging. Although the precise mechanisms of DR's neuroprotective functions are not fully elucidated, it has been suggested that DR exerts neuroprotective effects through
multiple pathways, such as modulating metabolic rates, reducing oxidative stress, increasing anti-inflammatory responses, regulating insulin sensitivity, and improving synaptic plasticity and neurogenesis. All of the molecular changes induced by DR may
directly or indirectly contribute to the regulation of neuroinflammation associated with aging and neurodegenerative diseases. DR may directly mitigate activation of glial cells and modulate expression of inflammatory cytokines and indirectly regulate
neuroinflammation by reducing inflammatory stresses, such as accumulation of toxic proteins and oxidative stress.

Considering the MouseAge Project https://www.fightaging.org/archives/2019/02/considering-the-mouseage-project/

Here, an update on the MouseAGE project from the popular science press. This initiative aims to produce a viable biomarker of aging based on visual inspection of mouse faces. Since age-related mortality in humans correlates fairly well with apparent age
of the face, and since machine learning techniques can be used to assess aging from photographs in an automated fashion, it seems reasonable to think that it might be possible to achieve a similar analysis in mice. If successful, it might by used to
speed up the assessment of potential rejuvenation therapies, a faster alternative to running life span studies. Given the low cost of development, it is worth a try as an alternative approach to the epigenetic clock and other biomarkers of aging under
development. The project was crowdfunded in 2017 and data collection began last year.

Vadim Gladyshev is asking lab scientists to whip out their smartphones and take photos. Not selfies, exactly, but snapshots of their lab mice. It's a fiddly task, Gladyshev admits: mice move fast, and need to be kept still for the camera. He suggests
grabbing them with one hand or taking them by the tail while they use their front paws to hold a rod. The impromptu photo shoots are all part of a crowdsourced effort to develop an algorithm that can help predict the biological age of a mouse from its
mug shot - information that could help researchers studying aging understand the connection between a person's biology and how old he or she looks.

Scientists now know, for example, that people who look younger than their years tend to live longer than people whose appearance more closely matches the time they've been alive. People are surprisingly good at predicting biological age when it comes to
fellow Homo sapiens. But pinpointing the biological age of mice is far more challenging. Instead, assessing the effect of anti-aging drugs in lab mice often involves taking blood samples and running expensive tests. Biomarkers such as DNA methylation
signatures and analyses of metabolites and biochemical measurements consume resources and run up costs. Alternatively, researchers may need to sacrifice mice in order to examine the internal effects of a compound.

The idea for a cheap and less wasteful alternative came to Gladyshev and Alex Zhavoronkov, founder of Insilico Medicine, a company specializing in artificial intelligence (AI) for aging research and drug discovery, a couple of years ago. The pair got to
chatting and came up with the idea of using a mouse's appearance as a marker of biological age - just as developers have attempted to do for humans. Mouse photo shoots have already been staged in labs across the US and Europe, and around 500 lab mice are
in the catalog. The team plans to release the algorithm publicly a few months from now and allow researchers to use it for free. But the project is still in the image-collection stage, as the more reference images it has, the better the algorithm will
perform. The team aims to collect images of 1,000 mice by March, but Gladyshev is planning to continue collecting until the project has sourced at least 10,000. "Future programs would tell whether one group of mice is biologically younger than another,
allowing us to more easily test interventions. Instead of waiting for mice to die, they can be quickly assessed for their potential to live longer."

100 Million Longevity Vision Fund Launches https://www.fightaging.org/archives/2019/02/100-million-longevity-vision-fund-launches/

A new fund to invest in companies working on aging recently launched, the 100 millions Longevity Vision Fund. From what has been said, and what was presented at the Longevity Leaders conference, it sounds very much as though the Longevity Vision Fund
principals wish to follow in the footsteps of Juvenescence, with an initial focus on small molecule drug discovery infrastructure. Unlike Juvenescence, it will probably continue to focus on established infrastructure technologies related to age-related
disease, such as diagnostics, and fairly safe work with modest benefits, such as stem cell therapies, rather than invest in any of the current attempts to produce rejuvenation therapies. Whether the strategy changes later, to shift to be more in line
with the rhetoric on the fund website, remains to be seen. Such a shift looks somewhat unlikely based on what is said in the article here, though the details given at the conference were more nuanced.


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