Fight Aging! Newsletter, August 19th 2019

My name is Jim Mellon, and I'm the chairman of Juvenescence, which is a company involved in the science of longevity. It is relatively recently formed, it is about a year and a bit old, but we've raised a significant amount of funding - nearly 160 million now - in the last year to advance the cause of longevity science. By the end of this year, we will have made 18 investments. Most of them are subsidiary companies of ours, so we control those companies. We give both development and financial backing to the scientist-entrepreneurs and institutions that we collaborate with.

I am fortunate to have two partners who have broad experience in the biotech and healthcare area, in particular Declan Doogan, who was the head of drug development at Pfizer for a long period, and then he worked at Amarin, which as you know is a very successful biotech company with a nearly 10 billion market valuation today. About four years ago, the three of us started a company called Biohaven, which is now listed on the New York Stock Exchange and has a valuation of about 2.5 billion. The company has approval for a drug for migraine, which will be on the market in the US next year. There is a good team of veteran drug developers who have come together to create this Juvenescence company, and we're very, very excited about it. We're the biggest investors in the company ourselves, on the same terms as other investors. We will take the company public in the first quarter of next year, barring market disasters, and probably on the US stock exchanges.

We're interested in this field of longevity science and able to raise significant funding because we've been in biotech for quite a long period of time, together, and created a number of companies. It seemed to be a natural outgrowth of the great developments that have occurred in the last few years. The unveiling of the human genome identified aging pathways that can now be manipulated. For the first time ever, you and I are in the cohort that is able to be bioengineered to live a healthier and longer life. It is still in a very primitive stage; we're in the internet dial-up era equivalent, but the science is advancing very quickly.

I always say that I wrote my first book on biotech seven years ago, it was called Cracking the Code, and since then we've had CRISPR/Cas9, which didn't exist seven years ago, we've had the cure for Hepatitis C, we've had artificial intelligence for the development of novel compounds. The latter of which is a key part of our strategy, as investors in In Silico Medicine, which I think you are familiar with. Then, of course, you have cancer immunotherapy, which didn't exist seven years ago, and is now a 100 billion / year industry. So what is going to happen in the next seven years? We don't know, but you can bet that it is going to be very, very good. So, if you want to regard it as a casino table, we're covering all the markers that we can with the funds that we've raised. We hope to raise a substantial further amount on the initial public offering of the company in the first quarter of next year, and that will give us enough resources to carry out five phase II trials without partners, so that we can get the maximum leverage on the products that we're developing.

So far we've invested in small molecules, which is the specialization of our team. For instance we have a senolytic drug in development in that area. We've also invested in stem cells; we're the largest investor in Mike West's company AgeX Therapeutics, which is now a public company in the US. We own about 46% of that company. Then via Lygenesis we've also got our first product going into patients in the first quarter of next year, sick patients in a phase II trial, for organ regeneration, regenerating the liver, using hepatocytes to seed lymph nodes to act as organic bioreactors to grow fully functioning liver tissue. The FDA has agreed to the protocol for doing that in sick patients, which is a remarkably fast path to demonstrating successful outcomes in that area. If that is successful, then we will look to regenerate other organs, in particular the thymus, which as you know is related to aging in a big way.

So we're moving very, very quickly. We've got great colleagues; Margaret Jackson from Pfizer is on our team. Howard Federoff, ex-Pfizer, is on our team. Annalisa Jenkins, who was head of drug development and research and development at Merck Serono, a very big company, is on our team. We've put it all together remarkably quickly. But we have experience in doing that, and so we're full of confidence. This is a remarkable time to be alive, and I want to be alive for at least another 20 or 30 years beyond what would be considered to be my allotted life span. The same is the motivating factor for my cofounders, Declan Doogan and Greg Bailey.

Working to extend life is an ethical cause. No-one can argue, successfully at least, that this isn't a good thing to do. There are some people who say "well, it is for the haves and not for the have-nots" but that is rubbish, because ultimately all these drugs will become generally available, and some of them already are. Metformin, which as you aware is a drug that has some anti-aging properties, costs essentially nothing. It is a generic drug. In the same as antibiotics and ulcer drugs and so forth were once expensive and are now very cheap, the same thing will happen to drugs for longevity. Gene therapy and stem cells is another matter, though, and that will probably be an expensive thing for some time to come. But undoubtedly, the cost will come down for those as well.

The other people who argue against work on aging talk about overpopulation; if there are all these old people, will there be enough room on the planet. Well the answer is, we're already alive, so we're not going to be adding to the population. You and I are already here. The big issue on population is how many children does each woman have around the world, and that figure is falling dramatically, to the point where we can see populations actually shrinking. Just as an example, if Japan doesn't all immigration, or doesn't have a baby boom, its population will fall from 126 million today to 50 million by the year 2100. So both those arguments, the haves versus the have-nots, and the overpopulation concern, are nonsensical arguments. In my view there is absolutely no reason why governments, institutions, the general population, the voting population, shouldn't be pushing really hard to make this happen.

Regarding the aging of the existing population and how to cope with it, the main point made by Aubrey de Grey, and other eminent scientists as well, is that if you treat the top of the cascade of damage in aging, then you are going to treat the underlying diseases of aging that pharmaceutical companies are trying to address. But for those pharmaceutical companies, it is a whack-a-mole exercise, so if you get one disease and that is cured, then you'll get another one, and they'll have to cure that one. Ultimately we become destabilized and we die, all of us. So let us try and treat aging as the central disease, and from that as the unitary disease, we'll be treating the cascade that follows from that.

Some people say it is hubris to target aging, but I think that this is because until relatively recently nothing worked. It has been an aspiration of human beings for millennia to find the fountain of youth, and nothing has worked. So people are skeptical about the fact that it might be working now. Why now rather than 20 years ago or 20 years in the future? But the fact is that it is now, and we need to seize the moment and rise to the challenge. We need much more funding to come into this area, and that funding will drive the science. We need many more advocates for this cause to come to the fore and spread the word, that this is going to be monumentally great for humanity.

In my own case, I've set up a charity with Andrew Scott, who wrote The 100 Year Life, and we do a Longevity Week in London. We did the first one last year, and we're doing the next one in November of this year, to spread the word. This will have a big societal impact, on consumption, on the way in which we look at the trajectory of life, but it is also going to have a major impact on us as human beings. In the past you'd have expected to live to about 85 or 90, the same with me, and now we're very likely to live to 110 or 120. So let's do it. Let's make it happen. I think that all of us, yourself, myself, have relatives, dear friends, acquaintances, who are suffering the indignities of aging as it currently exists. We would like to relieve that burden of suffering by extending the healthy span of life. The personal motivation is a very big factor. Here in Berlin, there are 300 or 400 people at this conference, and I imagine that all of them, beyond the business side of things, have an altruistic motivation for this as well. More people need to do it, so get on to it!

The elevator pitch for high net worth people thinking about investing in this space is that, first of all, we're at the front end of a huge upward curve. I said earlier on that this was like the internet dial up phase of longevity biotech. If you'd invested in the internet in the very early days, you'd be more than a billionaire now, you'd be one of the richest people on the planet. We're at that stage now, so the opportunity for investors is huge. But you could do both. You could invest in something like the SENS Research Foundation or the Buck Institute or one of those wonderful organizations that is trying to advance the cause, and at the same time invest in some of the companies that come out of those institutions. We've undertaken two joint ventures with the Buck Institute, we've made a couple of investments as a result of introductions by the SENS Research Foundation, including the organ regeneration program. So if you're a sensible billionaire, you will be putting some of your funds to work in a combination of a charitable enterprise that drives the science and the businesses themselves that come out of those enterprises.

DNA damage accumulation is critical for age-dependent loss of tissue-specific stem cell function. This type of accumulation is dependent on the attenuation of the DNA repair and response pathway. For example, DNA damage markers, such as histone H2A phosphorylation and comet tails, have been quantified in hematopoietic stem cells (HSCs) and muscle stem cells (MuSCs) from young and old mice and indicated strand breaks significantly accrue in HSCs and MuSCs during aging. It is therefore reasonable to suggest that an increase in the activity of DNA repair pathways may slow down or prevent the accumulation of age-related defects in stem cells and thereby promote the healthy function of aged tissues.

A gradual decline of the telomere length that occurs through the loss of telomerase during aging has been observed in mouse and human tissues. In the mouse model, the loss of telomerase displays telomere shortening, stem cell depletion, and impaired tissue injury responses. However, with telomerase reactivation, telomerase reverse transcriptase (TERT)-deficient mice extend telomeres and reverse degenerative phenotypes. Protection of telomeres 1A (Pot1a), a component of the Shelterin complex that protects telomeres, is highly expressed in young HSCs, whereas it progressively declines with age. In aged mice, treatment with exogenous Pot1a protein could reverse the HSC activity and sustain their self-renewal.

Increased expression of several cell cycle inhibitors, such as p53/p21, p16Ink4α, p19Arf, and p57Kip2 can lead to an essentially irreversible arrest of cell division and promote stem cell senescence. In MuSCs, HSCs, and neural stem cells (NSCs), the expression of p16Ink4α accumulates with age, but p16Ink4α repression through various methods can improve the function of aged stem cells and prevent cellular senescence. For example, silencing of p16Ink4α expression in geriatric satellite cells restores their quiescence and regenerative potential. In a potentially insightful study, researchers showed that autophagy is critical to the prevention of stem cell senescence by repressing the expression of p16Ink4α, and treatment with pharmacological rapamycin to stimulate autophagy could rejuvenate the MuSCs.

Many studies point that altered epigenetic marks of aging stem cells not only alter the transcriptional programs that dictate the function of the stem cells but also alter the potential differentiation towards distinct effector lineages. Recently, aberrant global and site-specific induction of active chromatin marks such as Hoxa9, has been investigated in aged satellite cells, while the inhibition or deletion of Hoxa9 can improve MuSC function and muscle regeneration in aged mice. Another example of successful rejuvenation comes from a study in which aged HSCs express a lower level of the chromatin organizer Satb1 than their young counterparts, while overexpression of Satb1 can improve their ability to generate lymphoid progeny via epigenetic reprogramming.

Signals can directly influence all aspects of stem cell functions including quiescence, proliferation, and differentiation. Signaling pathways involving p38-MAPK, janus kinase (JAK) / signal transducers and activators of transcription (STAT), Notch, and mechanistic target of rapamycin kinase (mTOR) contribute to the modulation of tissue stem cell functions, and their changes with age could affect tissue maintenance and repair systems. Hence, the proper modulation of these pathways is related to the reverse senescence of adult stem cells, which present the enhanced regenerative capacity of the tissues. For example, following overactivation of the p38α/β MAPK pathway, aged satellite cells are over-activated, and then increasingly generate their committed progenitors, while reducing self-renewal. However, pharmacological inhibition of p38α/β MAPK in aged satellite cells is able to restore the engraftment potential and improve their self-renewal ability by restoring asymmetric division.

It is known that tissue-specific stem cells are located in niches. The niche components can be considered somatic and stromal cells, immune cells, extracellular matrix (ECM), innervating neuronal fibers, and the vasculature. Although the niche structure varies among the different adult stem cell types, the stem cell niche provides essential cues to influence cell fate decisions. The aging of niche cells and age-dependent alterations in the components of stem cell niche are able to cause a loss of stem cell function. Fibroblast growth factor-2 (FGF-2), for example, is upregulated in the aged satellite cell microenvironment, whereas inhibition of FGF signaling can rescue the self-renewal capacity of old MuSCs. In addition, the cell surface receptor β1-integrin and the ECM protein fibronectin are dysregulated in aged MuSCs, and reconstitution of these components is able to restore the muscle regenerative capacity.

In addition to stem cell niche, aging also causes changes in circulating signals that directly or indirectly impact functions of tissue stem cells. These signals include soluble molecules secreted by any tissue in the body, which can be hormones, growth factors, and other signaling molecules or immune-derived signals secreted by infiltrating immune cells. Wnt ligand level is higher in old mouse serum and canonical Wnt signaling directly antagonizes Notch signaling in satellite cells. But Wnt inhibitors effectively restored the satellite cell function in aging, and a similar result is obtained in aged mesenchymal stem cells. The level of TGF-β is significantly increased in old human and mouse serum, which causes the damage and senescence of satellite cells. However, blockage of TGF-β signaling can reverse the activity of satellite stem cells, improving the myogenesis of aged mice.

Senescent cells accumulate with aging in several tissues of humans and animals, which is a common feature of age-related pathologies. Not only differentiated cells but also tissue-specific stem cells become senescence during aging. Moreover, the complex senescence-associated secretory phenotype (SASP) is highly expressed with accumulated senescent cells, which can alter the microenvironment and contribute to age-related pathologies. For example, the tissue regenerative capacity is impaired by the limited stem cell function because of their senescent state. And this decreased regenerative capacity is also regulated by the SASP that is secreted by senescent cells. Thus, the selective clearance of senescent cells and SASP suppression will be a promising therapy for age-related diseases. This concept has been successfully tested in physiologically aged mouse models.

As stem cells are the longest-living cells within an organism, stem cell aging is highly relevant as a driver of organismal aging, health, and longevity. In this review, we demonstrate that by targeting aging mechanisms, the aging associated phenotypes and functions of tissue-specific stem cells can be reversed. These restorative interventions hold promise for the possibilities of regenerative medicine and the treatment of many age-related diseases and dysfunctions.

Recent reports in mice show that cellular senescence can also regulate immune processes leading to the elimination of senescent cells (SnCs). In mouse models of hepatocarcinoma and liver fibrosis, restoring p53 function enables senescent cells to be eliminated by natural killer (NK) cells in part via NKG2D detection, while oncogenic RAS-induced senescence of hepatocytes promotes immune responses involving CD4+ T cells, neutrophils, and macrophages that lead to SnC removal. In mouse models of cutaneous wound repair, p53/p21- and p16-proficient SnCs are cleared after healing is complete. Notably, however, p53 and p16 are not required to trigger cellular senescence in human tissues/cells, and many senescence features are p53 or p16 independent, suggesting that additional mechanisms may regulate the interplay between SnCs and the immune system.

Despite evidence of immune surveillance and clearance of SnCs in mice, SnCs accumulate with age in patients and are found in inflamed and damaged tissues, premalignant lesions, and arrested tumors and after chemotherapy or radiotherapy. Persistent SnCs can contribute to age-associated pathologies and tissue dysfunction, including cancer. These effects have been attributed to the senescence-associated secretory phenotype (SASP), which includes inflammatory factors secreted by tissue-resident SnCs.

NKG2D ligands (NKG2D-Ls) are cell surface semaphores that mediate the immune recognition and clearance of cells that are transformed, damaged, stressed, or infected. NKG2D-Ls are mostly absent in healthy tissues. We previously observed an increase in NKG2D-L expression upon senescence induction in vitro in normal human fibroblasts. We measured the expression of NKG2D-L MICA and MICB in tumor samples from 10 patients with prostate cancer before and after mitoxantrone (MIT) treatment, which we previously showed induces cellular senescence based on cell cycle arrest and SASP markers. We found that after senescence-inducing genotoxic chemotherapy, residual tumors expressed significantly higher levels of MICA/B.

These results show that DNA-damaging chemotherapies induce tumors to develop a senescence phenotype associated with elevated levels of NKG2D-Ls. Although this may agree with the notion that SnCs upregulate NKG2D-Ls, it is surprising because NKG2D-Ls should promote the immune detection and clearance of those cells. Thus, other characteristics likely allow these SnCs to elude immune recognition and persist while expressing elevated levels of NKG2D-Ls.

As a first model, we induced cellular senescence by DNA damage or replicative senescence in normal human fibroblasts expressing wild-type p53/p16, or inactivated p53 (p53-), or knocked-down p16 (p16-). Although the p53/p21 and p16/pRb pathways are important effectors of cellular senescence, the upregulation of NKG2D-Ls in fibroblasts occurred regardless of p53 loss before or after senescence-inducing damage, and irrespective of their p16 status. Our other observations in which cells arrested and senesced with high levels of p16 but low levels of NKG2D-Ls, led us to postulate that the induction of NKG2D-L expression by SnCs may depend on the DNA damage response (DDR) but not on cell growth arrest per se.

SnC cycle arrest is carried out by cyclin-dependent kinase inhibitor (CDKI) p16 or p21. To mimic the senescence arrest elicited by these CDKIs, we overexpressed p16 or p21 in fibroblasts. We found that these cells showed limited changes in levels of NKG2D-L. This demonstrates that the expression of NKG2D-Ls is not a consequence of CDKIs' activation or senescence per se, but rather a response to damage that is separable from the growth arrest. Hence, p16 neither establishes nor triggers NKG2D-L expression, and the immunogenic program of cellular senescence can be dissociated from other senescence characteristics, including cell cycle arrest and p16 expression.

To explore how the fate of these different types of SnCs may depend on NKG2D-Ls, we cocultured leukocytes with SnCs or their presenescent counterparts, and measured cytotoxicity. We found that IL-2-preactivated primary natural killer (NK) cells were the main effectors of SnC cytolytic killing. Blocking the NKG2D receptor significantly prevented the killing of SnCs. These results show that NKG2D-Ls are key limiting factors that mediate the immune detection of damaged SnCs and orchestrate the balance between elimination/clearance and survival/persistence of SnCs.

A subset of damaged SnCs actively evades leukocyte recognition and killing. We had initially noticed that the elimination of damaged SnCs in leukocyte cocultures was never complete. So, we treated these persistent SnCs with fresh batches of leukocytes, and scored survival. We found that 70%-80% of the original persistent SnCs remained impervious to killing. Thus, persistent SnCs possessed inherent properties that allowed them to actively evade recognition and cytolysis. To characterize persistent SnCs, we compared NKG2D-L expression in SnCs that had not been exposed (naive) or had been exposed (persistent) to leukocytes. Surprisingly, persistent SnCs expressed equal or greater levels of intracellular NKG2D-L compared with naive cells. However, immunofluorescence showed strikingly diminished levels of NKG2D-Ls on the surface of persistent SnCs relative to naive one.

Since cancer cells can promote their immunoevasion by shedding NKG2D-Ls, SnCs may also shed NKG2D-Ls to elude immune detection and persist. We found that the cell culture media of senescent fibroblasts and epithelial cells contained soluble NKG2D-L MICA and that the media from persistent SnCs contained markedly higher levels of soluble NKG2D-Ls compared with naive counterparts. Thus, SnCs shed NKG2D-Ls regardless of cell type and p53 status, and this was amplified in persistent SnCs that avoided killing.

Because MMP3 was among the most upregulated MMPs across damaged SnCs, we used it as a marker of senescence detectable by immunofluorescence. In contrast to the high but variable MMP3 levels observed among naive SnCs, persistent SnCs consistently displayed intense MMP3 staining. To test the possibility that MMPs inhibition might preserve the cell surface presentation of NKG2D-Ls and thus enhance the killing of persistent SnCs, we used the broad-spectrum MMP inhibitor GM6001. GM6001 effectively blocked MICA shedding in a dose-dependent manner and increased cell surface NKG2D-Ls. Critically, GM6001 treatment of fibroblast and epithelial cancer SnCs prior to coculture with leukocytes markedly decreased SnC survival. Moreover, GM6001 treatment of already-persistent SnCs prior to a second round of leukocytes led to their near complete clearance.

In conclusion, our data show how oncogenic and tumor-suppressive drivers of cellular senescence act to regulate surveillance processes that can be circumvented to enable SnCs to elude immune recognition but can be reversed by cell surface-targeted interventions to purge the SnCs that persist in vitro and in patients. Since eliminating SnCs can prevent tumor progression, delay the onset of degenerative diseases, and restore fitness; since NKG2D-Ls are not widely expressed in healthy human tissues and NKG2D-L shedding is an evasion mechanism also employed by tumor cells; and since increasing numbers of B cells express NKG2D ligands in NKG2D receptor-deficient mice as they age, we propose that therapeutic interventions designed to increase cell surface presentation of NKG2D-Ls could be effective senolytic strategies to resensitize persistent SnCs to immune detection and rescue their clearance, whether in cancer or aging settings.

As our bodies age, our muscles and joints can become stiff, making everyday movements more difficult. This study shows the same is true in our brains, and that age-related brain stiffening has a significant impact on the function of brain stem cells. Researchers studied young and old rat brains to understand the impact of age-related brain stiffening on the function of oligodendrocyte progenitor cells (OPCs). These cells are a type of brain stem cell important for maintaining normal brain function, and for the regeneration of myelin - the fatty sheath that surrounds our nerves, which is damaged in multiple sclerosis (MS). The effects of age on these cells contributes to MS, but their function also declines with age in healthy people.

To determine whether the loss of function in aged OPCs was reversible, the researchers transplanted older OPCs from aged rats into the soft, spongy brains of younger animals. Remarkably, the older brain cells were rejuvenated, and began to behave like the younger, more vigorous cells. To fully understand how brain softness and stiffness influences cell behavior, the researchers investigated Piezo1 - a protein found on the cell surface, which informs the cell whether the surrounding environment is soft or stiff. "When we removed Piezo1 from the surface of aged brain stem cells, we were able to trick the cells into perceiving a soft surrounding environment, even when they were growing on the stiff material. What's more, we were able to delete Piezo1 in the OPCs within the aged rat brains, which lead to the cells becoming rejuvenated and once again able to assume their normal regenerative function."

Ageing causes a decline in tissue regeneration owing to a loss of function of adult stem cell and progenitor cell populations. One example is the deterioration of the regenerative capacity of the widespread and abundant population of central nervous system (CNS) multipotent stem cells known as oligodendrocyte progenitor cells (OPCs). A relatively overlooked potential source of this loss of function is the stem cell 'niche' - a set of cell-extrinsic cues that include chemical and mechanical signals. Here we show that the OPC microenvironment stiffens with age, and that this mechanical change is sufficient to cause age-related loss of function of OPCs.

Using biological and synthetic scaffolds to mimic the stiffness of young brains, we find that isolated aged OPCs cultured on these scaffolds are molecularly and functionally rejuvenated. When we disrupt mechanical signalling, the proliferation and differentiation rates of OPCs are increased. We identify the mechanoresponsive ion channel PIEZO1 as a key mediator of OPC mechanical signalling. Inhibiting PIEZO1 overrides mechanical signals in vivo and allows OPCs to maintain activity in the ageing CNS. We also show that PIEZO1 is important in regulating cell number during CNS development. Thus we show that tissue stiffness is a crucial regulator of ageing in OPCs, and provide insights into how the function of adult stem and progenitor cells changes with age. Our findings could be important not only for the development of regenerative therapies, but also for understanding the ageing process itself.

Frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS) are devastating neurodegenerative diseases characterized by the mislocalization and cytosolic accumulation of the predominately nuclear TAR DNA-binding protein 43 (TDP-43) in the central nervous system. The presence of TDP-43 neuropathology in ~97% of ALS and ~50% of FTLD cases provides a molecular link, showing both diseases to be on the spectrum of the TDP-43 proteinopathies.

A number of physiological functions are perturbed in FTLD and ALS, including impaired protein homeostasis, RNA dysmetabolism, and reduced nucleocytoplasmic transport of mRNAs and proteins. The cytoplasmic deposition of TDP-43 occurs concomitantly with the depletion of native TDP-43 from the nucleus, causing neurodegeneration in both FTLD-U and ALS by a combination of gain-of-function (GOF) and loss-of-function (LOF) mechanisms. Cytosolic aggregates are known to be intrinsically toxic and able to recruit nuclear TDP-43, exacerbating their deleterious effects by contributing to the nuclear LOF.

In this scenario, it is crucial for neurons to maintain TDP-43 protein homeostasis by the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway (ALP). Indeed, a progressive decrease in the efficiency of both protein degradation systems has been reported as a major factor contributing to FTLD-U and ALS onset in aging patients. This hypothesis is also supported by genetic evidence, as many of the mutations associated with FTLD and ALS affect genes involved in UPS- or ALP-mediated degradation. Recent studies showed that the cytosolic accumulation of TDP-43 is turned-over mainly by the UPS, with ALP contributing to its degradation when TDP-43 accumulates as intractable aggregates.

Here we found an early ROS production and caspase-3 activation in murine neuroblastoma N2A cells, following cytosolic transfection with preformed inclusions of human TDP-43 in the absence of any recruitment of the nuclear TDP-43 reservoir. Moreover, our data identify mitochondria as the main responsible sites for the alteration of calcium homeostasis induced by TDP-43 aggregates, which, in turn, stimulates an increase in reactive oxygen species and, finally, caspase activation. We also showed that the UPS and ALP systems are unable to efficiently degrade at least a fraction of the TDP-43 inclusions in neurodegenerative diseases.

People living with inflammatory bowel disease (IBD) have a three- to sevenfold higher risk of developing colon cancer. Researchers have now shown that precision editing of the bacterial populations in the gut reduces inflammation-associated colorectal cancer in mice. "The most significant finding in this study is that manipulating the intestinal microbiome is sufficient to affect the development of tumors. One could envision a time in which medications that change the behavior and composition of the bacteria that live in the gut will be part of the treatment for IBD."

In addition to colorectal cancer, long-standing IBD is associated with imbalances in the bacterial species that line the gut. "Our intestinal tract is teeming with microbes, many of which are beneficial and contribute to our overall health. Yet, under certain conditions, the normal function of these microbial communities can be disturbed. An overabundance of certain microbes is associated with increased risk for the development of diseases, including certain cancers." The strategy used in the study targets metabolic pathways that are only active during intestinal inflammation and only in some forms of bacteria, providing an Achilles' heel for reducing their abundance. The current study builds on work that found the approach prevented or reduced inflammation in a mouse model of colitis, while having no obvious effect on healthy control animals with balanced bacterial populations in their guts.

"For example, most E. coli bacteria are harmless and protect the human gut from other intestinal pathogens such as Salmonella, a common cause of food poisoning. However, a subset of E. coli bacteria produce a toxin that induces DNA damage and can cause colon cancer in research animals. We developed a simple approach - giving a water-soluble tungsten salt to mice genetically predisposed to develop inflammation - to change the way potentially harmful E. coli bacteria generate energy for growth. Restricting the growth of these bacteria decreased intestinal inflammation and reduced the incidence of tumors in two models of colorectal cancer. Tungsten is a heavy metal and should not be used by anyone due to its toxicity. This is a proof-of-concept study that will guide us in developing future drugs with similar activity and less toxicity."

Tissue aging is the gradual decline of physiological homeostasis accompanied with accumulation of senescent cells, decreased clearance of unwanted biological compounds, and depletion of stem cells. Senescent cells were cell cycle arrested in response to various stimuli and identified using distinct phenotypes and changes in gene expression. Senescent cells that accumulate with aging can compromise normal tissue function and inhibit or stop repair and regeneration. Selective removal of senescent cells can slow the aging process and inhibits age-associated diseases leading to extended lifespans in mice and thus provides a possibility for developing antiaging therapy.

To monitor the appearance of senescent cells in vivo and target them, a clearer understanding of senescent cell expression markers is needed. We investigated the age-associated expression of three molecular hallmarks of aging: SA-β-gal, P16INK4a, and retrotransposable elements (RTEs), in different mouse tissues at three different stages in the aging process (1 month, 12 months, and 24 months). Our data showed that the expression of these markers is variable with aging in the different tissues. P16INK4a showed consistent increases with age in most tissues, while expression of RTEs was variable among different tissues examined.

Increased β-gal staining in cerebellar Purkinje neurons might reflect locomotor incoordination that is often associated with aged individuals. Increased β-gal staining also was observed in the hippocampus and substantia nigra, which are major brain regions associated with neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, respectively. In addition, human aging is associated with reduced amounts of cerebrospinal fluid (CSF) and increased protein concentrations, which might be attributed to an aged choroid plexus. Thus, specific brain regions appear to be highly sensitive to an aging phenotype, which suggested that further investigations are warranted, especially for the choroid plexus and for the unique functions of CSF in healthy people and patients.

Similar to the brain, mouse kidneys demonstrated significant upregulation of the aging markers used in this study, especially in the renal cortex. It was surprising that the kidneys expressed a senescent phenotype earlier than any of the other organs included in this study. These findings might reflect the essential role of the kidney in the aging process. Previous studies have not focused on this relationship. The kidney is important in maintaining homeostasis of the body, suggesting that aging of the kidney is more likely to occur earlier than other organs and possibly the age-related decline of other organs might be a consequence of failure of the kidney to effectively eliminate circulating age-inducing molecules. Since elderly humans have less renal functional reserve and are more susceptible to chronic renal diseases, actions to preserve renal function might help to delay or alleviate aging-related consequences in the whole body.

We demonstrated that aging significantly influenced specific brain regions, the renal cortex, pulmonary bronchioles, and interstitial cells of the testes but had little or no effect on lung parenchyma, the liver, heart, and testicular seminiferous tubules. In conclusion, the gradual functional decline of peripheral organs might be a consequence of the aging brain or kidneys either through aging of neurons that influence these organs or through failure of the kidneys to eliminate age-associated molecules that occur due to environmental and genetic causes. Additionally, the age-dependent changes in RTE expression may be related to changes in function rather than directly associated with the aging process. The upregulation of RTEs in the mouse brain and kidneys might positively enhance the clearance of P16INK4a-positive cells.

Cognitive decline starts before conventional definitions of old age (often 65 years) and accelerates with aging and accumulation of comorbidities. Certain health events, such as stroke, can lead to profound changes in the cognitive trajectory such that there is a permanent "step change" in cognitive function. For 60 years a major concern has been that surgery might also drive long term changes in cognition. Yet studies investigating associations between surgery and long term cognitive outcomes have produced inconsistent results, with reports of cognitive harm, no effect, and cognitive improvement. Despite inconclusive evidence, considerable concern remains about the potential for surgery to induce cognitive impairment. Longer life expectancy implies an increasing number of surgical operations in older adults, hence a better understanding of the extent of any change in cognition after surgery is urgently required.

We use cognitive data from 7532 adults, investigating whether incident major surgical admissions are related to long term changes in the cognitive trajectory, using five waves of cognitive assessments spanning approximately 20 years, with adjustment for major medical admissions. To facilitate interpretation of results, we translate effect estimates to equivalent years of cognitive aging and relate changes to the effect of stroke, an event with an established impact on cognition. We primarily aimed to establish the mean population effect of major surgery on cognitive decline.

After accounting for the age related cognitive trajectory, major surgery was associated with a small additional cognitive decline, equivalent on average to less than five months of aging. In comparison, admissions for medical conditions and stroke were associated with 1.4 and 13 years of aging, respectively. Substantial cognitive decline occurred in 2.5% of participants with no admissions, 5.5% of surgical admissions, and 12.7% of medical admissions. Compared with participants with no major hospital admissions, those with surgical or medical events were more likely to have substantial decline from their predicted trajectory. In conclusion, major surgery is associated with a small, long term change in the average cognitive trajectory that is less profound than for major medical admissions. During informed consent, this information should be weighed against the potential health benefits of surgery.

It has become increasingly clear that epigenetics, including DNA methylation, histone modifications, and chromatin state, play a crucial role in the aging process. For example, by assessing changes in DNA methylation patterns, a person's age can be predicted within 5 years of accuracy. Histone modifications, including methylation and acetylation states, have been intimately linked to lifespan regulation. Together, these modifications dictate chromatin state, affecting both gene transcription and genome stability. Epigenetic changes occurring with age provide a tantalizing therapeutic target. In contrast to DNA mutations, epigenetic alterations represent reversible changes, offering the potential for a true "rejuvenating" therapeutic intervention. Of the various epigenetic alterations occurring with age, the influence of histone acetylation, a process balanced by the activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs), on lifespan regulation has been the most characterized, mainly due to the advent of HDAC inhibitors from the cancer biology field.

The exact means by which HDAC inhibitors extend lifespan has not been fully resolved; however, a number of possible mechanisms can be envisioned. One possible scenario is that HDAC inhibitors reverse the natural age-related changes occurring in the histone acetylation landscape. This is the most simple explanation for their benefits, supported by the observation that many acetylation marks on histones generally decrease with age and in certain age-related diseases. A second possible mechanism of HDAC inhibitors is that they may affect histones and nucleosomes to directly activate transcription of pro-longevity genes. This is supported by observations that an endogenous HDAC inhibitor, β-hydroxybutyrate (BHB), can increase acetylation in the promoter of the pro-longevity transcription factor FOXO3a resulting in its increased expression, and indeed, BHB's lifespan extending effects depend on HDAC genes.

A third possible mechanism through which HDAC inhibitors may increase lifespan is through hormesis. In this scenario, while high doses of HDAC inhibitors may be toxic, low doses would elicit activation of protective genes to regain homeostasis, ultimately improving function. This is supported by observations that flies treated with HDAC inhibitors show upregulation of heat shock protein chaperones, a class of genes that are usually upregulated under stress. A fourth possibility is that HDAC inhibitors may regulate lifespan by modifying the acetylation state of non-histone proteins, activating signaling cascades that promote longevity independent of histone modifications.

Despite the promising outlook of HDAC inhibitors for healthy aging, much work remains to be done to better understand their safety and how to minimize adverse side effects. Owing to their origins in the cancer biology field, many cell-type and dose-dependent negative effects of HDAC inhibitors on cell viability have been documented. Careful optimization of dose and drug pharmacokinetics should be made prior to pursuing any strategy in which HDAC inhibitors would be used as a prophylactic drug for healthy aging. More specifically, less-toxic versions of current drugs may be required. Understanding of the mechanism by which HDAC inhibitors extend lifespan is noticeably limited, and many mechanistic options remain. Deeper study of the specific modes of action of these compounds is necessary prior to their implementation as geroprotective compounds.

Normally, immune cells called macrophages will detect cancer cells, then engulf and devour them. In recent years, researchers have discovered that proteins on the cell surface can tell macrophages not to eat and destroy them. This can be useful to help normal cells keep the immune system from attacking them, but cancer cells use these "don't eat me" signals to hide from the immune system. Researchers had previously shown that the proteins PD-L1, CD47, and the beta-2-microglobulin subunit of the major histocompatibility class 1 complex, are all used by cancer cells to protect themselves from immune cells. Antibodies that block CD47 are in clinical trials. Cancer treatments that target PD-L1 or the PDL1 receptor are being used in the clinic.

Researchers now report they have found that a protein called CD24 also acts as a "don't eat me" signal and is used by cancer cells to protect themselves. "Finding that not all patients responded to anti-CD47 antibodies helped fuel our research to test whether non-responder cells and patients might have alternative 'don't eat me' signals. "You know that if cancers are growing in the presence of macrophages, they must be making some signal that keeps those cells from attacking the cancer. You want to find those signals so you can disrupt them and unleash the full potential of the immune system to fight the cancer."

The search showed that many cancers produce an abundance of CD24 compared with normal cells and surrounding tissues. In further studies, the scientists showed that the macrophage cells that infiltrate the tumor can sense the CD24 signal through a receptor called SIGLEC-10. They also showed that if they mixed cancer cells from patients with macrophages in a dish, and then blocked the interaction between CD24 and SIGLEC-10, the macrophages would start gorging on cancer cells. Lastly, they implanted human breast cancer cells in mice. When CD24 signaling was blocked, the mice's scavenger macrophages of the immune system attacked the cancer. Of particular interest was the discovery that ovarian cancer and triple-negative breast cancer, both of which are very hard to treat, were highly affected by blocking the CD24 signaling.

The other interesting discovery was that CD24 signaling often seems to operate in a complementary way to CD47 signaling. Some cancers, like blood cancers, seem to be highly susceptible to CD47-signaling blockage, but not to CD24-signaling blockage, whereas in other cancers, like ovarian cancer, the opposite is true. This raises the hope that most cancers will be susceptible to attack by blocking one of these signals, and that cancers may be even more vulnerable when more than one "don't eat me" signal is blocked.

Growth factors have become an important therapeutic option to avoid aging, because they are responsible for cell differentiation and maturation, being directly correlated with the minimizations of the topical esthetic changes resulting from age advancement. Growth factor proteins are naturally secreted by cells and interact directly or are sequestered by the surrounding extracellular matrix for presentation to cell surface receptors. The introduction of growth factors in certain damaged sites in the body seeking to stimulate regeneration is clinically related to regenerative medicine, where researchers intend to replace or repair damaged cells, tissues, and organs to effectively restore normal function.

Among the existing growth factors, we highlight the fibroblast growth factor (FGF), which induces the synthesis of type 1 collagen and therefore presents a relevant role in the process of skin aging control. Collagen is the protein responsible for the structure, elasticity, and firmness of the skin and it is produced by cells called fibroblasts. During the aging process, the proliferative and metabolic activity of fibroblasts decreases and their functions are impaired, leading to reduction of the synthesis of structural substances such as collagen, elastin, hyaluronic acid, and chondroitin. In addition, decreased levels of growth factors, reduced amount of collagen, abnormal accumulation of elastin, and reduction in the epidermal and dermal thickness were observed during the aging process.

The FGF family members increase the proliferation and activation of fibroblasts by stimulating the accumulation of collagen as well as stimulating endothelial cell division. With the aging process, fibroblasts have their activity diminished and consequently the synthesis and activity of proteins that guarantee elasticity and resistance such as elastin and collagen are also affected. Thus, in aged skin, there is a lower production of collagen by the fibroblasts and a greater action of the enzymes that degrade it. This lack of balance speeds up the aging process. Although the functions of FGFs are well characterized, their mechanisms of action are still not completely clear. It is known that it involves inter- and extracellular signaling pathways that may be related to the RAS-MAP kinases pathways, PI3K-AKT, PLC-γ, or STAT. Therefore, FGF cell signaling involves interactions with multiple cell signaling pathways and complex feedback mechanisms.

Activation of FGF-1 improves skin elasticity and induces the synthesis of collagen and elastin. One study investigated the impact of FGF-1 on skin cells; results showed that recombinant FGF-1 has a strong effect on cellular proliferation of keratinocytes and fibroblasts. FGF-2 reduces and prevents expression lines and wrinkles through the activation of new skin cells and stimulates the proliferation of cells of mesodermal, ectodermal, and endodermal origin, mainly fibroblasts and keratinocytes. Researchers aimed to evaluate an in vivo method for aged skin rejuvenation through direct injection of intradermal FGF-2. The following rejuvenating effects were observed: improvement of skin smoothness, atrophied skin thickness, and improved viscoelasticity. Keratinocyte growth factor (KGF) is a member of the FGF family. While most FGFs influence the proliferation and/or differentiation of various cell types, KGF appears to act specifically on epithelial cells. A study evaluating the ability of KGF to reduce the visible signs of aging. The results showed that eighteen of the twenty subjects experienced significant improvement.

Peripheral artery disease (PAD) is a narrowing of the arteries in the legs or arms. A new approach to generating new blood vessels to treat PAD takes advantage of the surprising combination of implantable biomaterial scaffolds and childhood vaccines. In models of mice with hindlimb ischemia (a severe form of PAD), the technique increased the concentration of T cells at the ischemic site and stimulated angiogenesis, blood flow, and muscle fiber regeneration for up to two weeks. "One of the most exciting aspects of this work is that it provides a new method of enhancing blood vessel formation that does not rely on traditional biologics, such as cells, growth factors, and cytokines, that are typically used to promote vascularization. Also, it more broadly suggests that advances in bioengineered T-cell therapies, which have traditionally been used to treat cancers, may be utilized to promote wound healing and regeneration."

The researchers focused on T helper 2 (TH2) cells, a type of immune cell that has been found to secrete molecules that promote blood vessel growth in addition to producing cytokines that initiate immune responses. TH2 cells are also the crucial "memory" element of vaccinations against pathogens. For reasons that are not yet fully understood, delivering a small amount of aluminum in a vaccine greatly enhances TH2 cell formation, and nearly all Americans receive aluminum-containing childhood vaccines that protect them from a variety of diseases. The researchers had a hunch that vaccinated people could potentially mount a stronger TH2 cell response if the right triggering antigen was introduced; and, if that antigen was incorporated into a biomaterial scaffold located near a blocked artery, TH2 cells could be recruited to the scaffold and release their angiogenesis-promoting compounds where they are needed to help treat ischemia.

Researchers injected mice with ovalbumin, the primary protein found in egg whites, to create a mild immune reaction like an infectious antigen, along with aluminum hydroxide. Two weeks later the mice got a "booster" of the same vaccine, and four weeks later they were implanted with an ovalbumin-containing scaffold in their ischemic hindlimbs. These mice displayed higher numbers of ovalbumin-specific TH2 cells and eosinophils (angiogenesis-promoting cells that are activated by TH2 cells) in their ischemic muscles than mice that received the implant without the priming vaccine. Vaccinated mice also displayed a lower level of tissue death, higher blood vessel density, greater blood perfusion, and more regenerating muscle fibers in their ischemic hindlimbs after two weeks than unvaccinated mice that received the implant.

Kizoo, part of the Forever Healthy Foundation, has announced today that it will be supporting biotech company LIfT Biosciences, a company that focuses on creating a new generation of cancer therapies that use our own immune systems. LIfT Biosciences is developing a new type of cancer immunotherapy approach that uses neutrophils to seek and destroy all types of solid tumors. Neutrophils are a particular type of white blood cell that protect us from infections and perform other functions. They comprise around 40 to 60 percent of the total number of white blood cells in our bodies and are the first immune cells to arrive during a bacterial infection.

The company is developing the world's first cell bank of neutrophils that are designed to seek and destroy any solid tumor, regardless of its particular strain and unique genetic makeup, providing a more universal approach to cancer. The cell bank would potentially be able to supply a range of cell therapies to deal with different types of solid tumors, and it uses a cell therapy system known as Neutrophil only Leukocyte Infusion Therapy (N-LIfT). The system uses an ex-vivo approach and could be more cost-effective than other approaches using leukocyte therapy.

The company is initially going after a form of pancreatic cancer known as pancreatic ductal adenocarcinoma (PDAC), which has a very low survival rate, with only 3% of patients diagnosed surviving for five years. The company is currently finishing up preclinical research prior to launching a human clinical trial. The goal of the trial will be to demonstrate remission in high unmet need solid tumour cancers by 2021, which will include pancreatic cancers such as PDAC.

The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that plays critical roles in the regulation of growth, metabolism, and aging. The mTOR protein kinase is found in two distinct protein complexes; mTOR complex 1 (mTORC1) integrates numerous environmental and hormonal cues, including the availability of amino acids, to regulate key anabolic processes including ribosomal biogenesis, protein translation, and autophagy, while mTOR complex 2 (mTORC2) plays a role in cytoskeletal organization and is a key effector of insulin/PI3K signaling. The pharmaceutical rapamycin, which acutely and robustly inhibits mTORC1, extends the lifespan in organisms including yeast, worms, flies, and mice, even when begun late in life or when treatment is intermittent.

While it has long been presumed that inhibition of mTORC1 by rapamycin mediates its beneficial effects on longevity, we and others have found that prolonged treatment with rapamycin also inhibits mTORC2, both in cell culture and in vivo in mice. However, inhibition of mTORC2 by rapamycin is limited to specific cell lines and tissues, most likely determined by the relative expression of FK506-binding proteins (FKBPs). In the nematode Caenorhabditis elegans, mTORC2 regulates metabolic processes via several distinct signaling pathways and can have positive or negative effects on lifespan depending on the tissue that is targeted, the temperature, and the food source.

Over the last decade, significant progress has been made in understanding the roles of both mTOR complexes in the regulation of key metabolic tissues. Less well understood is the role of mTOR complex signaling in the brain. mTOR Complex 1 is clearly an important regulator of neuronal behavior; hypothalamic mTORC1 is a key sensor of nutrient sufficiency and acute activation of hypothalamic mTORC1 suppresses food intake. In contrast, the role of brain mTORC2 signaling in the regulation of metabolism, health, and longevity has been less studied. mTORC2 signaling in the brain plays important roles in whole body metabolism, but the specific neuronal populations mediating these effects and the long-term implications for health and longevity remain to be elucidated.

Here, we show that loss of hypothalamic mTORC2 signaling in mice decreases activity level, increases the set point for adiposity, and renders the animals susceptible to diet-induced obesity. Hypothalamic mTORC2 signaling normally increases with age, and mice lacking this pathway display higher fat mass and impaired glucose homeostasis throughout life, become more frail with age, and have decreased overall survival. We conclude that hypothalamic mTORC2 is essential for the normal metabolic health, fitness, and lifespan of mice. Our results have implications for the use of mTORC2-inhibiting pharmaceuticals in the treatment of brain cancer and diseases of aging.

The risk of colorectal cancer (CRC) varies between people, and the cellular mechanisms mediating the differences in risk are largely unknown. Senescence has been implicated as a causative cellular mechanism for many diseases, including cancer, and may affect the risk for CRC. Senescent fibroblasts that accumulate in tissues secondary to aging and oxidative stress have been shown to promote cancer formation via a senescence-associated secretory phenotype (SASP).

Given that CRC is an age- and diet-related disease and that the cellular and molecular mechanisms that underlie adenomatous polyp initiation and transformation are only partly understood, we carried out a series of studies to determine whether senescence-associated mechanisms may play a role in the polyp-to-CRC sequence. In this study, we provide both correlative and functional evidence that senescent fibroblasts and an essential SASP factor, GDF15, induce physiological and molecular changes that promote the adenoma-carcinoma initiation and progression sequence in the colon.

We assessed the role of senescence and the SASP in CRC formation. Using primary human colon tissue, we found an accumulation of senescent fibroblasts in normal tissues from individuals with advanced adenomas or carcinomas in comparison with individuals with no polyps or CRC. In in vitro and ex vivo model systems, we induced senescence using oxidative stress in colon fibroblasts and demonstrated that the senescent fibroblasts secrete GDF15 as an essential SASP factor that promotes cell proliferation, migration, and invasion in colon adenoma and CRC cell lines as well as primary colon organoids via the MAPK and PI3K signaling pathways. In addition, we observed increased mRNA expression of GDF15 in primary normal colon tissue from people at increased risk for CRC in comparison with average risk individuals. These findings implicate the importance of a senescence-associated tissue microenvironment and the secretory factor GDF15 in promoting CRC formation.