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  • Follistatin Gene Therapy Doubles Muscle Mass in Mice
  • SYK Inhibitors as a Novel Class of Senolytics, Mechanisms of Action Yet to Be Determined
  • Cellular Senescence in Lung Disease
  • Videos from the 2019 Longevity Forum in London
  • Linking Inflammation and Mitochondrial Dysfunction in Endothelial Tissue
  • Lin28 as a Target for Nerve Regeneration
  • Mechanisms of Calorie Restriction and Intermittent Fasting
  • The Moonshot Venture Fellowship at Apollo Ventures
  • Jim Mellon Funds Aging Research at University of Oxford
  • Better Vaccines for Older People are a Poor Alternative to Better Immune Systems for Older People
  • Exercise Acts Through Wnt Signaling to Slow Brain Aging in Rats
  • The Latest on Hyaluronan in Naked Mole-Rat Longevity
  • Certain p53 Sequence Changes are Indicative of Species Longevity
  • Kingsley Advani on Investing in the Longevity Industry
  • Loss of NAD+ Implicated in Age-Related Circadian Rhythm Dysfunction

Follistatin Gene Therapy Doubles Muscle Mass in Mice

Follistatin is an inhibitor of myostatin. Blocking myostatin activity enhances muscle growth, with accompanying beneficial side-effects such as a loss of excess fat tissue. This is well proven. There are a good number of animal lineages (mice, dogs, cows, and so forth) resulting from natural or engineered myostatin loss of function mutations, and even a few well-muscled human individuals with similar mutations. A number of groups are at various stages in the development of therapies to either upregulate follistatin or inhibit myostatin. The latter is further along in the formal regulatory process: human trials have been conducted for myostatin antibody therapies. Meanwhile, first generation follistatin gene therapies, such as that pioneered by BioViva Science, are available at great expense through the medical tourism market, such as via Integrated Health Systems, with all too little data on their efficacy.

In a world in which gene therapies become cheap and reliable, which will happen over the next ten to twenty years, follistatin upregulation will likely be one of the more widely available enhancement therapies. Who doesn’t want more muscle, less fat, and a better metabolism, and all of that lasting for longer into later life? Unfortunately, gene therapy platforms are at present not all that efficient when it comes to systemic delivery throughout the body, at least not without a great deal of optimization to the specific use case. It is true that targeting muscle can be more a matter of scores of relatively unoptimized intramuscular injections rather than some form of infusion, but in both cases the cost is presently prohibitive for most people, and results in humans are yet to be robustly quantified. Expectations on safety are at present influenced more by the large numbers of mammalian myostatin loss of function mutants than by clinical data.

All of this said, it remains the case that work continues in laboratories to produce well muscled mice via follistatin gene therapies. The research noted here is an example of the type, a study that is little different from those performed in mice more than a decade ago. A few new assessments are made, and are interesting in and of themselves. Nonetheless, the wheels of science turn slowly indeed.

Gene therapy in mice builds muscle, reduces fat

Building muscle mass and strength can take many months and be difficult in the face of joint pain from osteoarthritis, particularly for older people who are overweight. A new study in mice, however, suggests gene therapy one day may help those patients. The research shows that gene therapy helped build significant muscle mass quickly and reduced the severity of osteoarthritis in the mice, even though they didn’t exercise more. The therapy also staved off obesity, even when the mice ate an extremely high-fat diet.

The research team gave 8-week-old mice a single injection each of a virus carrying a gene called follistatin. The gene works to block the activity of a protein in muscle that keeps muscle growth in check. This enabled the mice to gain significant muscle mass without exercising more than usual. Even without additional exercise, and while continuing to eat a high-fat diet, the muscle mass of these “super mice” more than doubled, and their strength nearly doubled, too. The mice also had less cartilage damage related to osteoarthritis, lower numbers of inflammatory cells and proteins in their joints, fewer metabolic problems, and healthier hearts and blood vessels than littermates that did not receive the gene therapy. The mice also were significantly less sensitive to pain.

One worry was that some of the muscle growth prompted by the gene therapy might turn out to be harmful. The heart, for example, is a muscle, and a condition called cardiac hypertrophy, in which the heart’s walls thicken, is not a good thing. But in these mice, heart function actually improved, as did cardiovascular health in general. Longer-term studies will be needed to determine the safety of this type of gene therapy. But, if safe, the strategy could be particularly beneficial for patients with conditions such as muscular dystrophy that make it difficult to build new muscle.

Gene therapy for follistatin can mitigate the systemic metabolic inflammation and post-traumatic arthritis in high-fat diet-induced obesity

Obesity-associated inflammation and loss of muscle function play critical roles in the development of osteoarthritis (OA); thus, therapies that target muscle tissue may provide novel approaches to restoring metabolic and biomechanical dysfunction associated with obesity. Follistatin (FST), a protein that binds myostatin and activin, may have the potential to enhance muscle formation while inhibiting inflammation. Here, we hypothesized that adeno-associated virus 9 (AAV9) delivery of FST enhances muscle formation and mitigates metabolic inflammation and knee OA caused by a high-fat diet in mice. AAV-mediated FST delivery exhibited decreased obesity-induced inflammatory adipokines and cytokines systemically and in the joint synovial fluid. Regardless of diet, mice receiving FST gene therapy were protected from post-traumatic OA and bone remodeling induced by joint injury. Together, these findings suggest that FST gene therapy may provide a multifactorial therapeutic approach for injury-induced OA and metabolic inflammation in obesity.

SYK Inhibitors as a Novel Class of Senolytics, Mechanisms of Action Yet to Be Determined

Senescent cells accumulate with age, and this accumulation is an important contributing cause of aging. These errant cells secrete a potent mix of signal molecules that spur chronic inflammation and tissue dysfunction. Animal studies demonstrate that targeted removal of as little as a third of senescent cells in old individuals can produce a sizable reversal of many aspects of aging, as well as of a broad range of age-related diseases. A number of companies have been funded to commercialize senolytic therapies, those capable of selective destruction of senescent cells. Therapies present under development target a range of mechanisms, such as Bcl-2 family influence over apoptosis, and markers, such as p16 and senescence-associated beta-galactosidase.

At this early stage in the development of a senolytics industry, in which comparatively few classes of senolytic treatment exist, any discovery of a novel senolytic mechanism is likely to produce sizable rewards for the organization and researchers involved. Hence many research groups are either digging deeper into the biochemistry of cellular senescence, in search of gold, or screening large numbers of compounds for senolytics that might work in novel ways. Today’s open access paper is an example of the second class of initiative. The authors note their discovery of a senolytic small molecule that employs none of the known mechanisms of senolysis, but nonetheless can push senescent cells to self-destruct via apoptosis.

This state of comparative ignorance about how a compound functions is one of the interesting outcomes that can result from screening compound libraries. A team finds a compound that works to kill senescent cells, and they can determine whether or not it works through known mechanisms employed by other senolytics, but if it doesn’t, then a fair amount of effort lies ahead. It may well take years to understand exactly how this new senolytic works to selectively provoke apoptosis in senescent cells. In this context, the discussion section of the paper is well worth a closer read; it gives a sense of the complexity of the challenge.

Identification of SYK inhibitor, R406 as a novel senolytic agent

Selective clearance of senescent cells has been suggested to induce rejuvenation and longevity. In animal models, senolytic drugs have been shown to delay several age-associated disorders, to improve physical and cognitive function, and to extend lifespan. Because known senolytic drugs have limited diversity for their mode-of-action and affect change in a cell-type-specific manner, novel senolytic drugs are needed to improve efficacy and expend medical application against senescent cells.

Major classes of senolytic drugs typically focus on inhibiting pro-survival pathways or triggering pro-apoptosis signaling in senescent cells. The combination of dasatinib and quercetin, which reduced p21, PAI-2, and BCL-xL, and Navitoclax (ABT263), which targets the Bcl-2 family, belong to this class of senolytics. In other classes, the mimicry of forkhead box protein O4 (FOXO4) peptide selectively disrupted the p53-FOXO4 interaction, which induced p53-dependent apoptosis in senescent cells. Recently, a HSP90 inhibitor was identified as a novel class of senolytic drugs that downregulated the phosphorylation of PI3K/AKT, an anti-apoptotic factor. Despite intensified efforts to develop drugs targeting senescent cells, however, the number of senolytic agents is still limited in comparison with the number of drugs against other age-related diseases like cancer or fibrosis.

In this study, using high-throughput screening to measure the variation of cell proliferation and reactive oxygen species (ROS) levels, we identified a novel senolytic agent R406, also known as tamatinib. This agent was effective in the replicative senescence model of diploid human dermal fibroblasts. R406 induced the caspase-9-mediated intrinsic apoptotic pathway, similar to other known senolytic drugs; however, R406 did not significantly change the level of Bcl-2 family in senescent cells. Alternatively, R406 inhibited the phosphorylation of focal adhesion kinase (FAK) as well as p38 mitogen-activated protein kinase (MAPK), which both regulate cell survival. Our results demonstrate that R406 is a new class of senolytics that targets multiple regulatory pathways for senescent cell survival.

Cellular Senescence in Lung Disease

Today’s open access paper is a review of what is known of the role of cellular senescence in lung disease. With the development of senolytic therapies that can selectively destroy senescent cells, all conditions in which senescent cells contribute meaningfully to pathology may soon be effectively treated. Senescent cells accumulate with age in all tissues, and while never a sizable fraction of all cells, even a comparatively small number of senescent cells can cause chronic inflammation and tissue dysfunction. They secrete a mix of inflammatory signals, growth factors, and other molecules that has a sizable effect on the behavior of surrounding cells. In the short term, this behavior is a necessary part of wound healing and cancer suppression, among other activities, but when sustained over the long term, this contributes to the degeneration and diseases of aging.

Taken in the broader context of medical research as a whole, senescence is still poorly mapped, and its role in all too many conditions is not explored in any detail. There is only so much research funding, and only so many research teams. The hundreds of age-related conditions and scores of different tissues in the body are being explored with some sense of prioritization, but a great deal of work remains to be accomplished. The lung in an organ for which the role of cellular senescence in disease been more extensively investigated in recent years, largely because senescent cells are implicated in fibrosis, and fibrotic lung diseases have no truly effective treatments at this time. One of the first human trials of a senolytic therapy targeted idiopathic pulmonary fibrosis, and further, some very interesting animal studies have examined the more general decline of lung function with age, and its reversal through senolytic therapy.

Cellular Senescence in the Lung: The Central Role of Senescent Epithelial Cells

It is thought that cellular senescence contributes to developmental processes including promoting remodeling, inflammation, infectious susceptibility, and angiogenesis as well as fundamental processes, such as wound healing and tissue regeneration. Herein, senescent cells which fulfilled their action are removed from the interfered tissue via infiltrating immune cells. However, if senescent cells persist, these cells might foster age- and disease-associated physiological dysfunction, particularly through a progressively changing secretory profile. With this respect, cellular senescence is now considered an important driving force for the development of chronic lung pathologies, particularly chronic inflammation observed in lungs of aging patients and of patients suffering from asthma, chronic obstructive pulmonary disease, or pulmonary fibrosis. The accumulation of senescent cells in lungs has disadvantageous consequences. Understanding the mechanisms driving induction of cellular senescence as well as the mechanisms mediating pathology-promoting effects of senescence may offer new treatment strategies for chronic lung diseases.

Age-related changes in lung morphology include enlargement of small airways and a decreased alveolar surface tension, finally leading to a compliant distensible lung. Furthermore, senescent cells with increased senescence-associated secretory phenotype (SASP) secretion accumulate with age in adult lungs; these cells exert autocrine and paracrine effects resulting in increased inflammation, induced stem cell dysfunction, and/or senescence of neighboring cells. Most importantly, the age-related increase in senescent lung cells, together with ‘immune senescence’, namely the lack of inflammatory cells to respond to SASP, result in an ineffective or slowed clearance of senescent cells, a progressively altered local environment, and subsequently tissue aging or development of age-related diseases.

Considerable in vitro and preclinical in vivo data support a deleterious impact of senescence on vascular endothelial cells finally resulting in the failure of the endothelium to perform its normal, physiologic functions. It has been demonstrated that chronic clearance of senescent cells with senolytic drugs (e.g., dasatinib or quercetin), that selectively induce death of senescent cells or genetic clearance of p16-expressing endothelial cells, improves vascular phenotypes.

Repetitive injury, especially to the pulmonary epithelium, is considered a central factor in the development of various lung diseases. Herein, the senescence of the respiratory epithelium is regarded as a central process for the initiation and progression of related lung diseases, particularly in pulmonary fibrosis and experimental lung fibrosis models. Human lung tissues from lung fibrosis (idiopathic pulmonary fibrosis, IPF) patients were shown to harbor numerous senescent epithelial cells as revealed by prominent SA-β-gal and p16 staining. IPF related epithelial senescence was closely associated with the SASP factors IL-1β, IL-6, IL-8 and TNF-α, which were already correlated with pulmonary fibrogenesis. Therefore, the current hypothesis is that alveolar epithelial injury imposed on senescent epithelial cells leads to aberrant wound healing and the secretion of high levels of growth factors and chemokines that foster the activation of adjacent cells, including endothelial cells and fibroblasts, and fibrogensis.

In a preclinical model of radiation-induced pneumopathy, clearance of senescent cells with a senolytic drug (ABT-263) efficiently reduced senescent cells and reversed pulmonary fibrosis. This, of course, would even limit the diminishing epithelial regenerative capacity, as well as associated SASP-mediated effects on adjacent lung cells as a central aspect in the development of lung injury. Therefore, targeting particularly senescent lung epithelial cells was suggested as a promising option for pulmonary fibrosis. Moreover, treatment of irradiated mice with ABT-263 almost completely reversed pulmonary fibrosis, even when the initiation of ABT-263 treatment was delayed until fibrosis was established. This means that unlike other known radiation protectants and mitigators, which were usually needed to be applied before or shortly after radiotherapy, senolytic drugs such as ABT-263 have the potential to be used as an effective, novel treatment of radiation-induced side complications such as inflammation and fibrosis, even after the lung injury develops into a progressive disease.

Videos from the 2019 Longevity Forum in London

I am a few months late in noting this: videos from last year’s Longevity Forum, one of the events in the Longevity Week held in London in November 2019, in what now seems an entirely different world, were posted online earlier this year. The Longevity Forum is organized by Jim Mellon and allies, a part of his diverse efforts to advance the growth of a longevity-focused medical industry capable of turning back aging and significantly lengthening healthy life spans.

The Forum is focused on non-profits, regulatory concerns, and government policy rather than on industry, but there are nonetheless interesting presentations. The purpose here is to help educate decision makers and the public as to what researchers and the longevity industry is working on, the plausible emergence of much longer lives in the near future, and to suggest that some thought should go into smoothing the path to the clinic ahead of time.

This is a big tent sort of a venture, and you’ll find people working on rejuvenation therapies rubbing shoulders with those who limit their considerations to exercise programs for seniors. Then throw into the mix noted non-profit fundraisers, policy makers, and other interested parties. I’ve noted a couple of the presentation videos; there are others, so by all means take a look at the full list.

Panel: How can the UK add five years of healthy lifespan by 2030

This panel will explore the recent advances in pro-longevity therapies, including small molecules, stem cells, regenerative medicine , microbiome and gene therapy. All of these are, to varying degrees, in human trials and the combination of these exciting developments and the fact that ageing pathways have been proven to be malleable, make the bioengineering of human beings to live longer and more robustly a strong likelihood, rather than an historically improbable aspiration. Indeed, it is clear that the science of biogerontology is rapidly catching up with the desire of most of us to live longer and in better health.

Aubrey de Grey: Scientists, check, Investors, check, Next up, policy makers

Aubrey de Grey delivers a keynote on the next steps for longevity for policy makers. Dr Aubrey de Grey is a biomedical gerontologist based in Mountain View, California, USA, and is the Chief Science Officer of SENS Research Foundation, a California-based 501(c)(3) biomedical research charity that performs and funds laboratory research dedicated to combating the ageing process.

Linking Inflammation and Mitochondrial Dysfunction in Endothelial Tissue

Today’s open access research implicates an imbalance of mitochondrial dynamics in the direction of too much mitochondrial fission in the age-related chronic inflammation observed in endothelial cells of the cardiovascular system. Every cell carries a herd of hundreds of mitochondria, the distant descendants of symbiotic bacteria now integrated as cellular components. The primary task of mitochondria is to generate adenosine triphosphate (ATP), a chemical energy store used to power cellular operations, but they are involved in many core cellular processes. Mitochondria are removed when damaged by the quality control mechanism of mitophagy, and replicate by fission in order to make up their numbers. Mitochondria are very dynamic structures: they pass around component parts, fuse together, and split apart constantly.

A balance between mitochondrial fission and fusion is necessary for optimal cellular function. A sizable portion of the age-related decline in mitochondrial function may be due to an imbalance in the direction of excessive fusion, leading to large mitochondria that become worn and damaged but are resistant to recycling via mitophagy. The proximate cause of this issue appears to be changes in gene expression and protein levels, such as NAD+, or MFF and PUM2, but links to deeper, more fundamental causes of aging remain to be established in a concrete way. It isn’t as simple as just a matter of too much fusion, however, as the research here illustrates. Certainly, changes in mitochondrial dynamics are involved in a number of important issues in aging, and imbalance in either direction can be problematic.

Researchers Uncover Link between Blood Vessel Inflammation and Malfunctioning Cellular Powerhouses

The vast majority of cells in the human body contain tiny power plants known as mitochondria that generate much of the energy cells use for day-to-day activities. Like a dynamic renewable resource, these little power plants are constantly dividing and uniting in processes called fission and fusion. The balance between fission and fusion is critical for health – especially cardiovascular health. Now, scientists have uncovered a novel mechanism by which abnormalities in mitochondrial fission in endothelial cells – the cells that line the inner surface of blood vessels – contribute to inflammation and oxidative stress in the cardiovascular system. They further show how the fission-fusion balance can be stabilized to lower inflammation using salicylate, the main active ingredient in everyday pain-relieving drugs like aspirin.

In endothelial cells, chronic inflammation causes mitochondria to become smaller and fragmented. This damaging process is mediated by a molecule known as dynamin-related protein 1 (Drp1). Normally, Drp1 plays a helpful role in maintaining fission-fusion balance. When cells are stressed by inflammation, however, it steps up fission activity, resulting in mitochondrial fragmentation. Researchers stimulated inflammatory pathways that produced mitochondrial fragmentation. They then examined the effects of blocking Drp1 activity and expression. These experiments showed that in cells, Drp1 inhibition suppresses mitochondrial fission, NF-κB activation, and inflammation. Reductions in fission and inflammation were also observed in cells following NF-κB inhibition, as well as in follow-up studies in mice genetically engineered to have less Drp1.

The researchers next determined whether the anti-inflammatory drug salicylate could also reduce mitochondrial fragmentation. Salicylate works by blocking the activity of multiple inflammatory molecules, including NF-κB. As anticipated, in mice, treatment with salicylate attenuated inflammation and mitochondrial fragmentation via its effects on NF-κB and downstream pathways.

Mitochondrial Fission Mediates Endothelial Inflammation

Endothelial inflammation and mitochondrial dysfunction have been implicated in cardiovascular diseases, yet, a unifying mechanism tying them together remains limited. Mitochondrial dysfunction is frequently associated with mitochondrial fission/fragmentation mediated by the GTPase Drp1 (dynamin-related protein 1). Nuclear factor (NF)-κB, a master regulator of inflammation, is implicated in endothelial dysfunction and resultant complications. Here, we explore a causal relationship between mitochondrial fission and NF-κB activation in endothelial inflammatory responses.

In cultured endothelial cells, TNF-α (tumor necrosis factor-α) or lipopolysaccharide induces mitochondrial fragmentation. Inhibition of Drp1 activity or expression suppresses mitochondrial fission, NF-κB activation, vascular cell adhesion molecule-1 induction, and leukocyte adhesion induced by these proinflammatory factors. Moreover, attenuations of inflammatory leukocyte adhesion were observed in Drp1 deficient mice. Intriguingly, inhibition of the canonical NF-κB signaling suppresses endothelial mitochondrial fission. Mechanistically, NF-κB p65/RelA seems to mediate inflammatory mitochondrial fission in endothelial cells. In addition, the classical anti-inflammatory drug, salicylate, seems to maintain mitochondrial fission/fusion balance against TNF-α via inhibition of NF-κB.

In conclusion, our results suggest a previously unknown mechanism whereby the canonical NF-κB cascade and a mitochondrial fission pathway interdependently regulate endothelial inflammation.

Lin28 as a Target for Nerve Regeneration

Researchers here show that the gene Lin28 regulates axon regrowth. In mice, raised levels of Lin28 produce greater regeneration of nerve injuries. Past research has investigated Lin28 from the standpoint of producing a more general improvement in regenerative capacity. It improves mitochondrial function, thus providing additional energy for cellular growth and replication. Researchers here employ a viral vector to deliver Lin28 to mice, which is a first step on the long road towards clinical applications. Practical therapies remain years in the future, however.

“Our findings show that Lin28 is a major regulator of axon regeneration and a promising therapeutic target for central nervous system injuries. We became interested in Lin28 as a target for neuron regeneration because it acts as a gatekeeper of stem cell activity. It controls the switch that maintains stem cells or allows them to differentiate and potentially contribute to activities such as axon regeneration.”

To explore the effects of Lin28 on axon regrowth, researchers developed a mouse model in which animals expressed extra Lin28 in some of their tissues. When full-grown, the animals were divided into groups that sustained spinal cord injury or injury to the optic nerve tracts that connect to the retina in the eye. Another set of adult mice, with normal Lin28 expression and similar injuries, were given injections of a viral vector for Lin28 to examine the molecule’s direct effects on tissue repair.

Extra Lin28 stimulated long-distance axon regeneration in all instances, though the most dramatic effects were observed following post-injury injection of Lin28. In mice with spinal cord injury, Lin28 injection resulted in the growth of axons to more than three millimeters beyond the area of axon damage, while in animals with optic nerve injury, axons regrew the entire length of the optic nerve tract. Evaluation of walking and sensory abilities after Lin28 treatment revealed significant improvements in coordination and sensation.

Mechanisms of Calorie Restriction and Intermittent Fasting

This open access paper provides a good high-level overview of what is known of the molecular mechanisms underpinning the beneficial response to calorie restriction and intermittent fasting. In short-lived species, quite sizable gains in life span are possible, though this is not the case for longer-lived species such as our own. The metabolic responses to calorie restriction and intermittent fasting are not the same; they appear to function through an overlapping set of mechanisms, such that intermittent fasting without reduction in overall calories can still improve health and extend life.

The ultimate goal for animal studies on calorie restriction (CR) and intermittent fasting (IF) is to identify the conserved molecular mechanisms that can extend the healthspan of humans. Healthspan, the period of life that is free from disease, is measured by examining declines of functional health parameters and disease states. Because healthspan is a multifactorial complex phenotype that is significantly affected by genotypes (G) and environmental factors (E) as well as complicated interactions between them (G × E), measuring healthspan often gets complicated.

Delayed functional aging in one parameter is not always necessarily linked to the extension of healthspan in different health parameters. In fact, by depending on the types of health parameters and experimental approaches, different healthspan results were observed from the studies that used the same long-lived mutant animals. Unlike healthspan, lifespan is unequivocally recorded by simply following the mortality of individual organisms. Lifespan extension in animal models is strongly correlated with a decrease in morbidity and an increase in health. Therefore, although we believe that results of health-related parameters from animal CR/IF studies are likely to be translatable to human healthspan, we will focus on the mechanisms of lifespan extension.

Although not complete, studies for the last two decades on CR have provided a great amount of details about the mechanisms of CR. Recent advances in omics and bioinformatic techniques followed by organism level genetic perturbation analyses significantly extended our knowledge on the molecular mechanisms that mediate lifespan extension by CR. A current understanding is that CR works through the key nutrient and stress-responsive metabolic signaling pathways that include IIS/FOXO, TOR, AMPK, Sirtuins, NRF2, and autophagy. While these pathways regulate CR independently, cross-talks among these pathways as well as upstream master networks such as circadian clock were also suggested to regulate lifespan extension by CR.

Although the number of reports on IF is less than CR, recent studies clearly demonstrated that IF also extends lifespan in both vertebrate and invertebrate model organisms. However, there is still a lack of comprehensive understanding for the mechanisms responsible for lifespan extension by IF. As nutrient-dependent interventions, CR and IF were suggested to share a common strategy: the reduction of caloric intake and nutrients that limit longevity. In fact, CR and IF also result in common metabolic and physiological changes in multiple tissues and organs. For example, ketone bodies, insulin sensitivity, and adiponectin are increased while insulin, IGF-1, and leptin are decreased. Overall inflammatory response and oxidative stress are reduced by both regimens. They also cause similar behavioral changes such as increased hunger response and cognitive response.

Accordingly, it is widely accepted that common molecular mechanisms may mediate the lifespan extension by CR and IF. A proposed model for the mechanisms underlying the lifespan extension by CR and IF relatively follow the notion that both CR and IF alter the activity of common key metabolic pathways, namely, TOR, IIS, and sirtuin pathways. However, there must be independent mechanisms as well due to one major difference between CR and IF in that IF aims to extend lifespan without an overall reduction in caloric intake by taking advantage of the molecular pathways that respond to fasting.

The Moonshot Venture Fellowship at Apollo Ventures

One of the more productive strategies undertaken by advocates and venture firms in the longevity industry is to put effort into the creation of companies, rather than waiting for companies to arise. This is still a small, young industry, without the sizable ecosystem that attends more mature areas of biotechnology, and thus many, many lines of research that might be productively developed into therapies targeting the mechanisms of aging remain stuck in academia. For investors and advocates to change this state of affairs requires building connections in the research community, introducing researchers and entrepreneurs, and helping research teams to make the transition into forming a company for commercial development. Investors are somewhat more efficient in conducting this sort of program, given that they have meaningful funding to hand, and so it is good to see more venture firms, such as Apollo Ventures, undertaking initiatives in company formation.

The idea that something might be done about age-related diseases using a repair-based approach targeting the root causes of aging was, for the most part, not taken seriously just a decade ago. What has happened in the last few years to increase acceptance and confidence in the idea?

I think the biggest change is the progress in aging science – over the last 10 years, scientific knowledge has evolved very quickly and reached a point where we finally understand what aging means on a molecular level and how we can fight it. Also, accelerating technologies like CRISPR and AI have catalyzed the entire longevity industry. At Apollo Ventures, we are leveraging this scientific progress to build the companies that will finally target the root cause of age-related diseases.

Can you tell us a little bit about the Moonshot Venture Fellowship?

The Moonshot Venture Fellowship is a 12-month program designed to give scientists the experience and support to create, launch, and build a venture-backed life science company based on outstanding science. For a scientist with a passion for translating research into medicines that make a difference for patients, the Moonshot Fellowship is an accelerated path to the skills to be a leader in life science companies. Our industry is a very young one. Thus, we believe that company building is needed to build up our industry. In the Moonshot Venture Program, either very senior pharma executives or biotech entrepreneurs are coming to us with an specific idea for a new company, or smart and ambitious postdocs who don’t have a specific idea for a company but unique insights and expertise in a specific area of the longevity field.

Traditionally, there has been somewhat of a disconnect between basic research and spinning that off into a biotech company capable of developing and delivering a therapy to market. How exactly is the Moonshot Venture Fellowship helping to bridge that gap?

The postdocs that we hire do exactly that. Most of them are coming out of universities and have significant expertise in aging science when they join our program. They have about 6 months of time to speak with everybody in their field, visit conferences, and read papers. Together with us, they evaluate the best technologies and ideas they find during their research. Our team’s expertise and long biotech experience is a great source to come up with a promising development plan. We help with tasks like IP evaluation, technology licensing, indication selection, and drug development plans. When all evaluations are positive, we found a company jointly with our fellows. Our support does not stop with the foundation of the company. We continue to be deeply engaged in the development of the company. Fundraising in our broad co-investor network and recruiting are two good examples where we can be really helpful for young companies.

Many promising startups fall foul of the “valley of death” before they can deliver to market and become profitable. How can programs such as the Moonshot Venture Fellowship help to mitigate this issue?

A program like ours can help to mitigate that issue, because apart from the scientific evaluation, we have the expertise, manpower and capital to commercialize such technologies. We are convinced that a clear clinical strategy and simply knowing who are the right co-investors for a project keep promising technologies from “drying out”. Our team has co-invested with all the experienced biotech VCs. We actively fundraise for our companies in our network so that the team can focus on what they are good at, i.e. developing promising therapeutics for age-related diseases.

What do you see based on your experience as being the greatest bottleneck to getting rejuvenation biotechnology based approaches to aging from the bench to the bedside?

It is definitely, first and foremost, money. However, the situation is getting better quickly, as more and more VCs and institutional investors realize that the longevity field is developing real technologies, solving a very important problem and the biggest business opportunity out there.

Jim Mellon Funds Aging Research at University of Oxford

Jim Mellon is doing a fair amount to help push the research and medical communities towards the development of therapies to slow and reverse the progression of aging. He is quite vocal in the business community, and is one of the founders of Juvenescence, very much involved in building portions of a longevity-focused biotechnology industry. He wrote a book on that topic as a part of convincing the broader investment community that this is an important new field. He has set up conferences, both for industry and for the broader community, such as the Longevity Forum. Here is an example of another approach, which is to fund institutional research programs to advance the state of the science.

We are delighted to announce that Jim Mellon (1975, PPE), British investor and philanthropist, has gifted 1 million to support and advance the study of Longevity Science at Oxford, and specifically at Oriel. The gift will establish the Mellon Longevity Science Programme at Oriel to help the most vulnerable in society by advancing research into health resilience in ageing populations. The gift is the largest of its kind dedicated to Longevity Science to a UK university, making Oriel and Oxford a focal point for efforts to improve future health resilience by boosting the immunity and healthspan of ageing populations. More specifically, the gift will support the work of Professor Lynne Cox, George Moody Fellow in Biochemistry at Oriel, and a principal investigator in the Department of Biochemistry. Her lab studies the molecular basis of human ageing, with the aim of reducing the morbidity and frailty associated with old age through better health resilience.

“There has never been a more important time to address the frailty of human health. The COVID-19 pandemic has highlighted the huge economic and social costs connected to the lack of immune resilience in our increasingly ageing population and the need for greater scientific research into this area. Boosting immunoresilience among the most vulnerable in society and advancing healthspan are critical to helping more people reach their potential as well as, more urgently, improving our collective resilience in the face of future pandemics. Oxford’s leadership in the field of research and understanding of the ageing process makes it a natural home to advance longevity science and support the growth of the longevity industry, and I am proud to support this work.”

Better Vaccines for Older People are a Poor Alternative to Better Immune Systems for Older People

The paper here offers a good overview of recent research and development aimed at improving the effectiveness of vaccines in old people. Vaccines are only poorly effective in the old because of the age-related decline of the immune system. A great deal of effort, with only some success, has gone into trying to improve vaccine effectiveness in older populations. Even if tinkering with vaccines boosts the percentage of patients who exhibit an immune response, however, that response is always going to be more anemic than that of a younger person, given the effects of aging on the immune system. This time and funding would perhaps be better directed towards ways to reverse the decline of the immune system, rather than towards the discovery of ever more complex ways of provoking the age-impaired immune system into a response.

Infectious diseases are a major cause for morbidity and mortality in the older population. Demographic changes will lead to increasing numbers of older persons over the next decades. Prevention of infections becomes increasingly important to ensure healthy aging for the individual, and to alleviate the socio-economic burden for societies. Undoubtedly, vaccines are the most efficient health care measure to prevent infections. Age-associated changes of the immune system are responsible for decreased immunogenicity and clinical efficacy of most currently used vaccines in older age. Efficacy of standard influenza vaccines is only 30-50% in the older population.

Several approaches, such as higher antigen dose, use of MF59 as adjuvant and intradermal administration have been implemented in order to specifically target the aged immune system. The use of a 23-valent polysaccharide vaccine against Streptococcus pneumoniae has been amended by a 13-valent conjugated pneumococcal vaccine originally developed for young children several years ago to overcome at least some of the limitations of the T cell-independent polysaccharide antigens, but still is only approximately 50% protective against pneumonia. A live-attenuated vaccine against herpes zoster, which has been available for several years, demonstrated efficacy of 51% against herpes zoster and 67% against post-herpetic neuralgia. Protection was lower in the very old and decreased several years after vaccination.

Recently, a recombinant vaccine containing the viral glycoprotein gE and the novel adjuvant AS01B has been licensed. Phase III studies demonstrated efficacy against herpes zoster of approx. 90% even in the oldest age groups after administration of two doses and many countries now recommend the preferential use of this vaccine. There are still many infectious diseases causing substantial morbidity in the older population, for which no vaccines are available so far. Extensive research is ongoing to develop vaccines against novel targets with several vaccine candidates already being clinically tested, which have the potential to substantially reduce health care costs and to save many lives. In addition to the development of novel and improved vaccines, which specifically target the aged immune system, it is also important to improve uptake of the existing vaccines in order to protect the vulnerable, older population.

Exercise Acts Through Wnt Signaling to Slow Brain Aging in Rats

Researchers here report on the application of various forms of exercise program to aged rats, followed by observing the effects on age-related cognitive impairment and related changes in the biochemistry of the brain. Wnt signaling, connected to a range of important cellular processes related to regeneration and tissue maintenance, is noted as one of the important pathways altered by exercise. This isn’t any great secret, I should say. Wnt signaling is well studied, and regenerative therapies based on manipulation of Wnt signaling are at a fairly advanced stage of development. Samumed has treatments in late stage clinical trials, for example.

Down-regulated Wnt signaling is involved in brain aging with declined cognitive capacity due to its modulation on neuronal function and synaptic plasticity. However, the molecular mechanisms are still unclear. In the present study, the naturally aged rat model was established by feeding rats from 6 months old to 21 months old. The cognitive capacity of aged rats was compared with young rats as the controls and the aged rats upon 12-week exercise interventions including treadmill running, resistance exercise, and alternating exercise with resistance exercise and treadmill running. Wnt signaling was examined in hippocampal tissues of the rats from different groups.

Results indicated that the expression of Dickkopf-1 (DKK-1) as an antagonist of Wnt signal pathway, the activation of GSK-3β, and the hyperphosphorylated Tau were markedly increased as the extension of age. Meanwhile, higher phosphorylated β-catenin promoted neuronal degradation of aged rats. In contrast, three kinds of exercise interventions rescued the abnormal expression of DKK-1 and synaptophysin in hippocampal tissues of the aged rats. In particular, 12-week treadmill running suppressed DKK-1 up-regulation, GSK-3β activation, β-catenin phosphorylation, and hyperphosphorylated Tau. In addition, the down-regulated PI3K/AKT and Wnt signal pathways were observed in aged rats, but could be reversed by resistance exercise and treadmill running. Moreover, the increased Bax and reduced Bcl-2 levels in hippocampal tissues of aged rats were also reversed upon treadmill running intervention.

Taken together, down-regulated Wnt signaling suppressed PI3K/Akt signal pathway, aggravated synaptotoxicity, induced neuron apoptosis, and accelerated cognitive impairment of aged rats. However, exercise interventions, especially treadmill running, can attenuate their brain aging process via restoring Wnt signaling and corresponding targets.

The Latest on Hyaluronan in Naked Mole-Rat Longevity

Naked mole-rats live nine times as long as similarly sized rodents, and are near immune to cancer. Researchers have for some years investigated the biochemistry of this species, in search of mechanisms that might be applied to improve health and longevity in other mammals, or form the basis for cancer therapies. Teams have looked into many different areas: mitochondrial function; better DNA repair; a greatly attenuated senescence-associated secretory phenotype; more efficient operation of cancer-suppression genes; and a heavier form of hyaluronan. Researchers here show that this heavier form of hyaluronan is protective of cells, and can produce this protective effect in human cells as well as naked mole-rat cells.

The longest-living rodent, the naked mole-rat (NMR) (Heterocephalus glaber), has a maximum lifespan of more than 30 years, which is fivefold greater than predicted by body mass. NMR does not show increase in mortality rates for at least 18 years, and seems to be protected from age-related deterioration such as metabolic decline, diabetes, and osteoporosis. These features indicate that NMR has evolved efficient anti-aging mechanisms. However, although NMR is increasingly appreciated as a model for aging research, how they resist aging processes remains largely unknown.

An important NMR-specific anti-cancer mechanism is early contact inhibition (ECI). Cultured NMR fibroblasts are hypersensitive to contact inhibition and stop proliferating at relatively low cell density in a hyaluronan (HA)-dependent manner. HA plays a role in supporting tissue structure and regulating cellular signaling pathways, effects that depend on its polymer length. Dynamic regulation of the amount and polymer length of HA is implicated in diverse biological processes including cell proliferation, cell migration, and inflammation. In healthy tissues, most of HA is of high-molecular-mass (HMM-HA). In pathological circumstances, significant fragmentation of HA occurs, giving rise to low-molecular-mass HA. NMR produces very-high-molecular-mass hyaluronan (vHMM-HA), much longer than HA in other mammalian species. However, it is still not clear whether HA of exceptionally high polymer length is functionally different from regular HMM-HA.

The observations that HA exhibits polymer length-dependent cytoprotective effect and that long-lived NMR produces vHMM-HA lead to a hypothesis that additional polymer length of NMR-HA confers superior cytoprotection that could contribute to the NMR’s longevity. Here, we show that vHMM-HA has superior cytoprotective properties compared to the shorter HMM-HA. It protects not only NMR cells, but also mouse and human cells from stress-induced cell-cycle arrest and cell death in a polymer length-dependent manner.

The cytoprotective effect is dependent on the major HA-receptor, CD44. We find that vHMM-HA suppresses CD44 protein-protein interactions, whereas HMM-HA promotes them. As a result, vHMM-HA and HMM-HA induce opposing effects on the expression of CD44-dependent genes, which are associated with the p53 pathway. Concomitantly, vHMM-HA partially attenuates p53 and protects cells from stress in a p53-dependent manner. Our results implicate vHMM-HA in anti-aging mechanisms and suggest the potential applications of vHMM-HA for enhancing cellular stress resistance.

Certain p53 Sequence Changes are Indicative of Species Longevity

Scientists here expand upon prior research indicating that longer-lived species tend to exhibit certain types of sequence difference in the tumor suppressor gene p53 – a gene also involved in many other processes relevant to aging. One might compare this with past studies that examine the number of copies of this gene in long-lived, larger species. Elephants have many copies of p53, for example, which might go long way towards explaining why they don’t exhibit higher cancer rates despite their great size, and thus greater number of cells.

The p53 protein is a well-known tumor suppressor and TP53 is the most often mutated gene in human cancers. On the cellular level, decreased p53 functionality is essential for cellular immortalization and neoplastic transformation. However, the role of variations in the p53 amino acid sequence on the organism level has not been studied systematically. Here, we presented an in-depth correlation analysis manifesting the dependencies between p53 variations and organismal lifespan to address the role of p53 in longevity. To date, p53 expression has been detected in all sequenced animals from unicellular Holozoans to vertebrates, with the lone exception of the immortal Turritopsis jellyfish.

The results from Protein Variation Effect Analyzer show that the variability in lifespan among closely related species correlates with specific p53 variations. Long-lived organisms are characterized by in-frame deletions, changes, insertions or specific substitutions in the p53 sequence. It is likely that the changes imposed on p53 in long-lived species enable p53 to interact with different multiple protein partners to induce gene expression programs varying from those induced in species with relatively normal lifespan.

We can anticipate that these gene expression programmes would enable following changes: 1. more efficient tissue repair through autophagy, 2. loss of senescence, 3. enhanced clearance of senescent cells by the immune system, 4. enhanced regulation of intracellular reactive oxygen species (ROS) levels 5. improved resistance of mitochondria to ROS-induced damage or 6. loss of immune senescence that occurs in humans with age. All of the mentioned processes have been previously described as significantly contributing to longevity. Thus, long-lived organisms apparently have a different mechanism of protection against cancer and their lifespan is not limited by somatic cell senescence caused by active p53 protein, which is the case for other species with shorter lifespan as mentioned above.

We inspected TP53 gene sequences in individual species of phylogenetically related organisms that show different aging patterns. We discovered novel correlations between specific amino acid variations in p53 and lifespan across different animal species. In particular, we found that species with extended lifespan have characteristic amino acid substitutions mainly in the p53 DNA binding domain that change its function. These findings lead us to propose a theory of longevity based on alterations in TP53 that might be responsible for determining extended organismal lifespan.

Kingsley Advani on Investing in the Longevity Industry

Kingsley Advani is one of the more active angel investors in the growing longevity industry. This is still a young industry, and like many of people involved, whether as entrepreneurs or investors, Advani is motivated more by an interest in achieving progress in medical technology than in a return on investment. Though of course, investors who ignore that second point tend not to remain investors for all that long.

What do Juvenescence, Oisín Biotechnologies, Volumetric, and GEn1E Lifesciences have in common? Yes, they are all companies that fit squarely in the burgeoning Longevity sector, but they are also companies invested in by Kingsley Advani, a US-based British investor who has made the extension of human life one of his key investment categories. In addition to investing in more than 50 companies, Advani is also a financial supporter of non-profit longevity organisations including SENS Research Foundation, Methuselah Foundation, and the National University of Singapore.

I think that Juvenescence have a very sensible approach, they are very well capitalised and they have multiple shots on goal. They have companies in their portfolio that are working on areas like tissue regeneration, like LyGenesis, who are using lymph nodes as bioreactors, and companies like Insilico Medicine that are using deep learning for drug discovery. So they have a pretty wide range of shots on goal.”

“I invest in the longevity industry for the impact, because if you could extend the healthy lives of eight billion people, then it’s really a noble act. Secondly, I felt that longevity was underserved in terms of investment – a majority of these companies are privately funded and there’s a lack of attention from government, so I felt there was a gap in terms of private investment. I want to increase volume of investment in longevity companies and so I’ve been educating more private investors about longevity.”

Loss of NAD+ Implicated in Age-Related Circadian Rhythm Dysfunction

As for other aspects of metabolic regulation, circadian rhythm becomes increasingly disrupted with age. Researchers here provide evidence for falling NAD+ levels to be a proximate cause of this issue. NAD+ is important in the core activity of mitochondria, generation of energy store molecules to power cellular operations, but also acts on numerous other processes in the cell. Unfortunately the various mechanisms of synthesis and recycling of NAD+ falter as tissues age, though it is an open question as to how much of this is a matter of failing to maintain fitness versus more inexorable processes of aging. Data suggests that exercise programs in older individuals can do just as well, if not better, than approaches based on providing NAD+ precursors such as nicotinamide riboside as supplements.

Cellular levels of NAD+ decline with ageing, and boosting NAD+ production by administration of its precursors promotes youthful behavioural and physiological functions in mice. To investigate the role of NAD+ in circadian gene expression in mice, the authors gave mice drinking water that was supplemented with NAD+ precursors for 4 months and analysed circadian gene expression in the liver. This revealed that the expression pattern of approximately half of circadian-regulated hepatic genes changed upon NAD+ increase.

NAD+ is a cofactor for sirtuin deacetylases, which are known to promote healthspan and lifespan. Sirtuin 1 (SIRT1) regulates circadian rhythms by binding to the core clock complex – comprising the heterodimeric circadian transcription activator CLOCK-BMAL1 and its repressor PER2 – and driving PER2 deacetylation and subsequent degradation. Liver-specific Sirt1 knockout abrogated the changes in hepatic circadian gene expression that were observed when NAD+ levels were increased.

Next, the authors found that in the liver of old mice, chromatin occupancy of BMAL1 was decreased, which coincided with increased PER2 levels and decreased amplitude of circadian gene oscillations. Administration of NAD+ precursor to the old mice for 6 months restored BMAL1 chromatin binding and function to levels observed in young animals. In addition, late-night locomotor activity, normally reduced in old mice, was restored to youthful levels with NAD+ precursor administration. In summary, elevating NAD+ has the capacity to reverse ageing-associated dysfunction of circadian rhythms.