Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter, please visit: https://www.fightaging.org/newsletter/
Longevity Industry Consulting Services
Reason, the founder of Fight Aging! and Repair Biotechnologies, offers strategic consulting services to investors, entrepreneurs, and others interested in the longevity industry and its complexities. To find out more: https://www.fightaging.org/services/
- All Too Short Comments on the 10th Aging Research and Drug Discovery (ARDD) Meeting
- Dormant Neural Precursor Cells May Awaken Over Adult Life to Maintain the Brain
- Urolithin A Supplementation Improves Mitochondrial Function and Hematopoiesis in Mice
- A Continued Painfully Slow Assessment of the Dasatinib and Quercetin Senolytic Treatment in Human Trials
- Mitochondrial Epigenetics in Age-Related Mitochondrial Dysfunction
- Revisiting Bivalves for the Study of the Determinants of Species Lifespan
- Examining Lifestyle Correlations with Thymic Involution
- Short Term Fasting Enhances the Immune Function of Red Blood Cells
- Autophagy is Protective Against Hematopoietic Stem Cell Aging
- Towards Targeted Telomerase Gene Therapy
- The Damage Done by Non-Standard Scientific Controls
- Benefits of Calorie Restriction on Pancreatic Beta Cells
- Reviewing Evidence for Urolithin A Supplementation
- Inflammation in Early Alzheimer's Disease
- The Open Genes Database of Associations with Aging and Longevity
All Too Short Comments on the 10th Aging Research and Drug Discovery (ARDD) Meeting
I attended the 10th Aging Research and Drug Discovery (ARDD) conference in Copenhagen recently, alongside my Chief Scientific Officer at Repair Biotechnologies, Mourad Topors. If one wanted to take in all of the presentations and take notes, as I've done in the past, ARDD would be much more of a test of endurance than other longevity industry conferences. It is five 12 hour days, starting with networking at 8am, the last presentations going on past 8pm, and then socializing at nearby bars afterwards for the truly dedicated. This on top of jet lag for those coming in from the US in direction and Asia in the other. The intent of the organizers is for participants, and those following the livestream, to drop in for the topics that interest them, and take the time for other activities in between.
The mix of attendees was, as always, some combination of academics, the founders of biotech startups, visitors from Big Pharma, and investors, those being a mix of interested individuals and venture capitalists. Judging from discussions held in the corridors, the present view of the investment market for biotech startups is that while some people are raising funds with apparent ease, it is still not a great environment. Better than the start of the year, but not great. There were fewer institutional investors at ARDD than in past years, and the consensus appears to be to expect fiscal gloom until later in 2024. Expenditures are cut, timelines extended, and bridge rounds are raised, business as usual for lean times.
The Big Pharma interest in the conference varied from "to be honest, my boss told me an hour ago to come in and represent the company, I'm really not familiar with this," to department heads with interesting experience and well-considered positions on the field. As some of you may know, one of my areas of interest is the path to better gene therapies, and I had a lengthy conversation with the director of a gene therapy program in which our views aligned on many of the details. Viral vectors are going to be amazing in 2050, but are very much not amazing now; there would be a mass exodus from the development of mRNA therapies if only someone could find a way to deliver plasmids to the nucleus; the development of tissue-targeted delivery systems seems on the verge of becoming impressive, but still has a long way to go if your targets are small areas of the body; and so forth.
This year, I confess, I attended only a fraction of the many presentations in the program. Most of my time was taken up with networking. For those who didn't attend, I recommend looking through the program and waiting for the videos to be posted. There were some interesting talks. The role and details of cellular senescence in aging was a frequent topic. Both the academic and industry communities are rapidly digging in to the biochemistry of senescence, with new discoveries emerging and the debates shifting on a regular basis. The Deciduous Therapeutics program is becoming one of the most interesting in the industry, given that their approach to rousing the immune system to destroy senescent cells lasts for a considerable time following a single dose. At the same time, they are far enough along in their work that the supply of new details shared in public is drying up, as often happens.
We at Repair Biotechnologies shared that our LNP-mRNA therapy can rapidly reverse both atherosclerosis and nonalcoholic steatohepatitis (NASH) in animal models. We plan to submit our first pre-IND package later in the year. Maxwell Biosciences is making an appearance at most conferences these days as they ramp up their program; they produce a small molecule mimetic of the LL-37 antimicrobial peptide, a sort of too-good-to-be-true part of the innate immune system that improves just about every process the immune system touches when upregulated. It attacks bacteria, viruses, cancers, and even appears to improve aspects of tissue maintenance. Their program is focused on delivery as needed. It did occur to me that one could learn from the Minicircle approach to follistatin upregulation and use some form of long-lasting vector to turn a small volume of subcutaneous fat cells into a factory for LL-37, permanently upregulating it and its effects on immune defenses, but apparently this doesn't have the desired effect - hence the need for a mimetic rather than the original peptide.
Other fellow travelers on the conference circuit showing off their progress included some of the growing number of reprogramming ventures: Retro Biosciences, rapidly expanding their research footprint and likely to become a behemoth in the industry the next time they go out to seek investment; Life Biosciences, about which much the same might be said; the actual behemoth of Altos Labs; and smaller ventures such as Turn Bio. Epigenetic reprogramming to reset the biochemistry of aged cells is, as one might expect, another frequent topic at conferences these days. Arguably the majority of funding for research and development in the field of longevity is currently focused on forms of partial reprogramming, which at least offers the hope that a decade from now we'll have answers to all of the most important questions about this approach.
We do live in a barnstorming age for biotechnology, and so very much more can be accomplished than regulators would approve for widespread use. There are a lot of high-flying technical discussions going on behind the scenes. Anything that starts with "why can't we just..." usually ends with "well, we could, but it would be very hard to obtain approval." Passing through the regulatory process is, meanwhile, so very expensive than only the most conservative, safe, incremental programs have an easy road to finding the necessary funding. Biotech investors are, if anything, even more conservative than the regulators, very ready to anticipate difficulties and avoid investing in those programs.
To conclude, if you'd like a crash course on the state of the scientific field and the industry focused on treating aging as a medical condition, attending ARDD is one of the better options on the table.
Dormant Neural Precursor Cells May Awaken Over Adult Life to Maintain the Brain
Neural stem cells residing within a few regions of the mammalian brain divide to generate new daughter neurons throughout adult life, the process of neurogenesis. Neurogenesis is particularly associated with functions such as memory, which requires changes in brain state driven by the creation of new neurons and neural connections. Additionally, however, researchers have identified a population of dormant progenitor cells that can mature into neurons, more broadly distributed throughout the brain. This population can be diminished and eventually exhausted by that activity, but researchers hypothesize that it could nonetheless be a source of regenerative capacity for the aging brain if the remaining pool of dormant progenitor cells could be awakened.
More speculatively, this type of progenitor cell might be a good candidate for cell therapies aimed at improving function in the aging brain. If the mechanism of awakening is understood and production of the cell type possible, continual rounds of therapy might be undertakn. Still, such efforts to restore the brain are future concerns: it remains quite challenging to deliver any therapy to the brain, never mind very challenging forms of therapy such as those involving the production and quality control of cells.
The awakening of dormant neuronal precursors in the adult and aged brain
The mammalian brain is traditionally described as a network of neurons and glia, in which maturation and establishment of connectivity occur shortly after birth, followed by circuit refinement throughout the early part of life. Yet, there are exceptions concerning the timing of maturation because specific types of neurons are added progressively to the brain circuits during the adulthood. Some well-known neuronal "latecomers" are those originating from the brain areas designated as adult neurogenic niches.
Recent studies and new technology allowed researchers to update the current concepts of adult neurogenesis by revealing the existence of other types of neuronal precursors, which reside outside the neurogenic niches. Although generated during the embryonic development, these cell types retain post-mitotic immaturity until adulthood. During adulthood, such neuronal precursors, herewith referred to as "dormant precursors," eventually awaken and become adult-matured neurons (AM). Much about the awakening and maturation of dormant precursors is yet to be revealed. So far, several works in different mammalian species suggested that dormant precursors occupy numerous brain regions.
We previously demonstrated that, after awakening, dormant precursors undergo axonal sprouting, formation of synapses, and the progressive acquisition of functional input and output during the transition from precursor to AM. At the same time, we were puzzled to note that while many dormant precursors undertook the course of maturation during early adulthood, some cells remained immature throughout adulthood. Similar observation was also common in other mammalian species, including primates and humans.
Consequently, we questioned whether the precursors remaining dormant for most of a lifetime can actually eventually awake and follow a course of late maturation or whether they fail to awaken altogether. On the one hand, we speculated that the aging of the brain may hinder or completely impair the awakening. On the other hand, if late awakening and maturation were possible, this would imply that the old brain in mammalians is equipped with an unexplored source of young neurons.
Urolithin A Supplementation Improves Mitochondrial Function and Hematopoiesis in Mice
A number of supplement-based approaches have been demonstrated to modestly improve mitochondrial function with age. This includes the various ways to increase NAD levels using vitamin B3 derivatives, mitochondrially targeted antioxidants such as SkQ1, MitoQ, and SS-31, and other compounds such as urolithin A for which the mechanism causing improved mitochondrial function is not as well determined. There is an argument to be made that all of these compounds work because they in some way improve the operation of mitophagy, a mitochondrial quality control mechanism that senses worn and damaged mitochondria, before directing them to a lysosome for recycling. That sensing is complicated and incompletely understood, which makes it challenging to determine what exactly is going on under the hood.
We do know that mitochondrial function and mitochondrial quality control are improved by the practice of calorie restriction, as well as by the exercise needed to maintain physical fitness. This might lead us to suspect that these approaches to improving mitochondrial function will have smaller effects on life span in long-lived humans than in short-lived mice, as that is exactly what happens in the case of calorie restriction. Meanwhile, we have no intuition as to the size of the outcomes that might be achieved via complete replacement of mitochondria, which is to my eyes the most promising approach to mitochondrial rejuvenation, or via allotopic expression, producing backup copies of mitochondrial DNA, or via partial reprogramming, which resets problematic gene expression changes that occur with age and impair aspects of mitochondrial function.
New study: reversing aging in the blood stem cells and the immune system
The aging process is often accompanied by a decline in the proper functioning of the hematopoietic and immune systems, making older adults more susceptible to infections, blood disorders, and even tumor development. A new study focused on a key player in the blood system - hematopoietic stem cells (HSCs). These cells are responsible for generating various types of blood cells, playing a critical role in maintaining a healthy immune system. As we age, HSCs experience a decline in their ability to regenerate blood and show a preference for a specific type of cell lineage, which contributes to immune system dysfunction.
By introducing a natural compound called Urolithin A, which targets mitochondria - the energy powerhouses of cells - researchers were able to reverse the decline in HSC function. Mitochondria abnormalities were identified as a contributing factor to the aging of HSCs. Urolithin A acted as a mitochondrial modulator, effectively restoring the mitochondrial function within HSCs. Urolithins are not found in food; however, their precursors are. Urolithin A is the result of transformation of ellagic acids and ellagitannins by the gut microflora in humans.
The most interesting finding of this preclinical study was that this intervention not only rejuvenated the blood reconstitution capability of older HSCs but also improved immune system function in aged mice. When Urolithin A was incorporated as a dietary supplement, it not only revitalized the immune system's lymphoid compartments but also enhanced overall HSC performance. This translated to an improved immune response against viral infections, showcasing the potential of Urolithin A to combat age-related immune system decline.
Induction of mitochondrial recycling reverts age-associated decline of the hematopoietic and immune systems
Aging compromises hematopoietic and immune system functions, making older adults especially susceptible to hematopoietic failure, infections and tumor development, and thus representing an important medical target for a broad range of diseases. During aging, hematopoietic stem cells (HSCs) lose their blood reconstitution capability and commit preferentially toward the myeloid lineage (myeloid bias). These processes are accompanied by an aberrant accumulation of mitochondria in HSCs.
The administration of the mitochondrial modulator urolithin A corrects mitochondrial function in HSCs and completely restores the blood reconstitution capability of 'old' HSCs. Moreover, urolithin A-supplemented food restores lymphoid compartments, boosts HSC function and improves the immune response against viral infection in old mice. Altogether our results demonstrate that boosting mitochondrial recycling reverts the aging phenotype in the hematopoietic and immune systems.
A Continued Painfully Slow Assessment of the Dasatinib and Quercetin Senolytic Treatment in Human Trials
A single course of treatment with the combination of dasatinib and quercetin clears meaningful numbers of senescent cells from aged human tissues, and to much the same degree as it does in mice. In mice this treatment dramatically, rapidly reverses signs of age-related disease. The research community has known this for the better part of a decade, with ever more studies added over this time. Near every age-related condition is reversed to some degree via the use of senolytic therapies that can selectively clear senescent cells, with dasatinib and quercertin continuing to be one of the better treatments, comparing those with published data.
One might think that there would be a rush to demonstrate that this cheap drug and supplement combination works in humans, and could therefore be used widely to improve late-life health by reducing the burden of senescent cells in near every older person. But no. Only a few studies have been conducted, tentatively. Today's research materials report on another of these efforts, a small phase 1 clinical trial that tells us nothing about efficacy, and only what we already knew about safety, that dasatinib and quercetin are safe for older people to use at senolytic doses and dosage schedules. The incentives operating in the clinical development community are such that any cheap, existing drug is unlikely to receive much attention, no matter how good it is. Vast sums are devoted to making new senolytic drugs, while a drug that might achieve a great deal of good in the world is left on the shelf.
That situation won't change any time soon, but there is a role for philanthropy here. It would not require all that much in funding to run a half dozen informal, hundred-participant clinical trials, on the scale of the PEARL trial for rapamycin, to demonstrate that, yes, dasatinib and quercertin is as good as we suspect it to be. The purpose would not be to demonstrate this point to the FDA, as dasatinib is already approved and quercetin is a supplement, and so these could be very lean trials, absent all the regulatory overhead and its costs. The goal is rather to demonstrate the merits and safety of this senolytic therapy to the physicians who can choose to prescribe off-label.
Phase I Clinical Trial Shows Treatment Designed to Clear Senescent Cells in Alzheimer's Disease is Safe
Senescent cells are old, sick cells that cannot properly repair themselves and don't die off when they should. Instead, they function abnormally and release substances that kill surrounding healthy cells and cause inflammation. Over time, they continue to build up in tissues throughout the body contributing to the aging process, neurocognitive decline and cancer.
For the current study, the research team enrolled five participants aged 65 and older with symptoms of early-stage Alzheimer's disease. Participants received oral dasatinib plus quercetin over two consecutive days, followed by two weeks of no drugs. The cycle repeated six times for a total of 12 weeks. The research team also collected data on the safety and efficacy of the two drugs by monitoring side effects. They assessed biomarkers of senescence in cerebrospinal fluid (CSF) and blood, and also evaluated patients' cognition and brain images before treatment and after they completed the 12-week study. They found that both dasatinib and quercetin levels increased in the blood, and dasatinib was detected in the CSF in four subjects. Quercetin was not detected in the CSF of any participant. "We also determined that the treatment was safe, feasible and well-tolerated. There were no significant changes in brain function as determined by assessing memory and brain imaging to provide additional evidence that it is a safe therapy to evaluate further." Researchers also saw evidence to suggest that the combination therapy cleared amyloid from the brain and lowered inflammation in the blood. "However, we shouldn't over-interpret these results. There was a small number of people enrolled, there was no placebo arm to compare results."
Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial
Cellular senescence contributes to Alzheimer's disease (AD) pathogenesis. An open-label, proof-of-concept, phase I clinical trial of orally delivered senolytic therapy, dasatinib (D) and quercetin (Q), was conducted in early-stage symptomatic patients with AD to assess central nervous system (CNS) penetrance, safety, feasibility, and efficacy. Five participants (mean age = 76 years) completed the 12-week pilot study.
D and Q levels in blood increased in all participants. In cerebrospinal fluid (CSF), D levels were detected in four participants (80%) Q was not detected. The treatment was well-tolerated, with no early discontinuation. Secondary cognitive and neuroimaging endpoints did not significantly differ from baseline to post-treatment further supporting a favorable safety profile.
CSF levels of interleukin-6 (IL-6) and glial fibrillary acidic protein (GFAP) increased with trending decreases in senescence-related cytokines and chemokines, and a trend toward higher Aβ42 levels. In summary, CNS penetrance of D was observed with outcomes supporting safety, tolerability, and feasibility in patients with AD. Biomarker data provided mechanistic insights of senolytic effects that need to be confirmed in fully powered, placebo-controlled studies.
Mitochondrial Epigenetics in Age-Related Mitochondrial Dysfunction
The hundreds of mitochondria present in every cell in the body undertake the essential duty of producing chemical energy store molecules, adenosine triphosphate (ATP), used to power the cell. With age, mitochondria become less efficient and more damaged, generating oxidative stress and triggering inflammation while producing less ATP than is optimal. This is thought to be a major contribution to degenerative aging, though as for all contributions to aging, it requires a highly targeted way to improve mitochondrial function in order to determine just how important it is. That highly targeted therapy doesn't yet exist in a useful form. The most plausible near future candidate is transplantation of young, functional mitochondria.
Mitochondria are descended from ancient bacteria that became symbiotic with early cells. As such, they retain a small remnant circular genome, the mitochondrial DNA. In today's open access paper, researchers note that while the mitochondrial transcription machinery that produces proteins from DNA sequences is different from that of the nucleus, mitochondrial DNA is still subject to epigenetic marks that can change protein output. Epigenetic patterns on the genome are known to change with age, producing changes in protein levels that are some mix of harmful and adaptive. It is reasonable to think that epigenetic regulation of protein production can be just as involved in age-related declines in the mitochondria as it is in the nucleus.
Mitochondrial epigenetics in aging and cardiovascular diseases
Mitochondria are cellular organelles which generate adenosine triphosphate (ATP) molecules for the maintenance of cellular energy through oxidative phosphorylation. They also regulate a variety of cellular processes including apoptosis and metabolism. Of interest, the inner part of mitochondria - the mitochondrial matrix - contains a circular molecule of DNA (mtDNA) characterised by its own transcriptional machinery. As with nuclear DNA, mtDNA may also undergo nucleotide mutations that have been shown to be responsible for mitochondrial dysfunction.
During physiological aging, the mitochondrial membrane potential declines and associates with enhanced mitophagy to avoid the accumulation of damaged organelles. Moreover, if the dysfunctional mitochondria are not properly cleared, this could lead to cellular dysfunction and subsequent development of several comorbidities such as cardiovascular diseases (CVDs), diabetes, respiratory diseases, as well as inflammatory disorders and psychiatric diseases.
As reported for genomic DNA, mtDNA is also amenable to chemical modifications, namely DNA methylation. Changes in mtDNA methylation have shown to be associated with altered transcriptional programs and mitochondrial dysfunction during aging. In addition, other epigenetic signals have been observed in mitochondria, in particular the interaction between mtDNA methylation and non-coding RNAs. Mitoepigenetic modifications are also involved in the pathogenesis of CVDs where oxygen chain disruption, mitochondrial fission, and reactive oxygen species (ROS) formation alter cardiac energy metabolism leading to hypertrophy, hypertension, heart failure, and ischemia/reperfusion injury.
In the present review, we summarize current evidence on the growing importance of epigenetic changes as modulator of mitochondrial function in aging. A better understanding of the mitochondrial epigenetic landscape may pave the way for personalized therapies to prevent age-related diseases.
Revisiting Bivalves for the Study of the Determinants of Species Lifespan
Mammals have a very wide range in life spans, and the study of mammals might be thought to be more relevant to efforts to extend human longevity than the study of other taxonomic classes. It is quite unclear at this time whether moving genes and mechanisms between mammalian species is likely to produce meaningful gains cost-effectively in the near future, but we certainly won't know if we don't try. Meanwhile, bivalves are another class with a large range in species life span. There is much to be said for undertaking the same sort of search for the determinants of species life span in bivalves as is presently ongoing in mammals. Having results for two quite different classes is likely to be more illuminating of the mechanisms of aging than the results for mammals alone.
Among Metazoa, bivalves have the highest lifespan disparity, ranging from 1 to 500+ years, making them an exceptional testing ground to understand mechanisms underlying aging and the evolution of extended longevity. Nevertheless, comparative molecular evolution has been an overlooked approach in this instance. Here we leveraged transcriptomic resources spanning thirty bivalve species to unravel the signatures of convergent molecular evolution in four long-lived species: Margaritifera margaritifera, Elliptio complanata, Lampsilis siliquoidea, and Arctica islandica (the latter represents the longest-lived non-colonial metazoan known so far). We applied a comprehensive approach - which included inference of convergent dN/dS, convergent positive selection, and convergent amino acid substitution - with a strong focus on the reduction of false positives.
Genes with convergent evolution in long-lived bivalves show more physical and functional interactions to each other than expected, suggesting that they are biologically connected; this interaction network is enriched in genes for which a role in longevity has been experimentally supported in other species. This suggests that genes in the network are involved in extended longevity in bivalves and, consequently, that the mechanisms underlying extended longevity are - at least partially - shared across Metazoa. Although we believe that an integration of different genes and pathways is required for the extended longevity phenotype, we highlight the potential central roles of genes involved in cell proliferation control, translational machinery, and response to hypoxia, in lifespan extension.
Examining Lifestyle Correlations with Thymic Involution
Thymocytes created in the bone marrow migrate to the thymus where they mature into T cells of the adaptive immune system. The thymus, unfortunately, loses active tissue with age, and this progressively reduces the pace at which new T cells are created. Lacking replacements, the adaptive immune system becomes increasingly made of up senescent, exhausted, and malfunctioning cells. This is an important component of immune aging.
Researchers here note that the presence of excess fat tissue correlates with greater atrophy of the thymus. Given that chronic inflammation is hypothesized to be important in driving this thymic involution, this result is not all that surprising. Excess visceral fat is metabolically active and generates inflammatory signaling through a range of mechanisms. Thus better lifestyle choices improve the odds of having more active thymic tissue in later life, and a less aged immune system.
Fatty degeneration of thymus (or thymus involution) has long been considered a normal ageing process. However, there is emerging evidence that thymic involution is linked to T cell aging, chronic inflammation, and increased morbidity. Other factors, aside from chronological age, have been proposed to affect the involution rate. In the present study, we investigated the imaging characteristics of thymus on computed tomography (CT) in a Swedish middle-aged population. The major aims were to establish the prevalence of fatty degeneration of thymus and to determine its associations with demographic, lifestyle, and clinical factors, as well as inflammation, T cell differentiation, and thymic output.
In total, 1,048 randomly invited individuals (aged 50-64 years, 49% females) were included and thoroughly characterized. CT evaluation of thymus included measurements of attenuation, size and a 4-point scoring system, with scale 0-3 based on the ratio of fat and soft tissue. A majority, 615 (59%) showed complete fatty degeneration, 259 (25%) predominantly fatty attenuation, 105 (10%) half fatty and half soft-tissue attenuation, while 69 (6.6%) presented with a solid thymic gland with predominantly soft-tissue attenuation. Age, male sex, high BMI, abdominal obesity, and low dietary intake of fiber were independently associated with complete fatty degeneration of thymus. Also, fatty degeneration of thymus as well as low CT attenuation values were independently related to lower proportion of naïve CD8+ T cells, which in turn was related to lower thymic output, assessed by T-cell receptor excision circle (TREC) levels.
Short Term Fasting Enhances the Immune Function of Red Blood Cells
A number of lines of research suggest that forms of calorie restriction and fasting can improve the function of the immune system. It is also noted that fasting can reduce the number of immune cells found in the circulation. The complement system is a part of the innate immune system, reacting to invading pathogens in order to rouse immune cells to action. Red blood cells play a part in the complement system, and researchers here show that fasting can improve the immune response despite a lower number of circulating white blood cells by improving the ability of red blood cells to trigger a response.
Fasting is known to influence the immune functions of leukocytes primarily by regulating their mobilization and redistribution between the bone marrow and the peripheral tissues or circulation, in particular via relocalization of leukocytes back in the bone marrow. However, how the immune system responds to the increased risk of invasion by infectious pathogens with fewer leukocytes in the peripheral blood during fasting intervention remains an open question.
We used proteomic, biochemical and flow cytometric tools to evaluate the impact of short-term intensive fasting (STIF), known as beego, on red blood cells by profiling the cells from the STIF subjects before and after 6 days of fasting and 6 days of gradual refeeding. We found that STIF, by triggering the activation of the complement system via the complement receptor on the membrane of red blood cells, boosts fairly sustainable function of red blood cells in immune responses in close relation to various pathogens, including viruses, bacteria, and parasites, particularly with the pronounced capacity to defend against SARS-CoV-2, without compromising their oxygen delivery capacity and viability.
Autophagy is Protective Against Hematopoietic Stem Cell Aging
Hematopoietic stem cells in the bone marrow give rise to red blood cells and immune cells. Like all stem cell populations, they become increasingly dysfunctional with age, however. In part this is damage to the stem cells themselves, but a sizable portion of the problem results from age-related damage and change in the niche of supporting cells that is needed to maintain a stem cell population. It is hoped that restoring stem cell function in older individuals will go a long way towards producing slowed aging and improved health. At present the research community is progressing towards this goal one stem cell population at a time, but it seems plausible that some discoveries will be broadly applicable to all stem cells in the adult body.
Aging of the hematopoietic system promotes various blood, immune, and systemic disorders and is largely driven by hematopoietic stem cell (HSC) dysfunction. Autophagy is central for the benefits associated with activation of longevity signaling programs, and for HSC function and response to nutrient stress. With age, a subset of HSCs increases autophagy flux and preserves some regenerative capacity, while the rest fail to engage autophagy and become metabolically overactivated and dysfunctional. However, the signals that promote autophagy in old HSCs and the mechanisms responsible for the increased regenerative potential of autophagy-activated old HSCs remain unknown.
Here, we demonstrate that autophagy activation is an adaptive survival response to chronic inflammation in the aging bone marrow (BM) niche. We find that inflammation impairs glucose metabolism and suppresses glycolysis in aged HSCs through Socs3-mediated impairment of AKT/FoxO-dependent signaling. In this context, we show that inflammation-mediated autophagy engagement can preserve functional quiescence by enabling metabolic adaptation to glycolytic impairment.
Moreover, we demonstrate that transient autophagy induction via a short-term fasting/refeeding paradigm normalizes glucose uptake and glycolytic flux and significantly improves old HSC regenerative potential. Our results identify inflammation-driven glucose hypometabolism as a key driver of HSC dysfunction with age and establish autophagy as a targetable node to reset old HSC glycolytic and regenerative capacity.
Towards Targeted Telomerase Gene Therapy
Interestingly, telomerase upregulation to lengthen telomere length may turn out to be a decent match for the capabilities of lipid nanoparticle (LNP) delivery of messenger RNA (mRNA) as an implementation of gene therapy. This produces one to two days of expression which, by the sound of things, is enough to give telomeres enough of a boost in length to be worth the exercise, can be repeated as needed, is familiar to regulators, and the LNP field is energetically working towards variant LNPs that can target specific tissues and cell types.
The question is whether or not lengthening of telomeres via telomerase gene therapy is a good idea in humans. There is a lot of hype over telomere length, but given that telomeres shorten with each cell division, average telomere length in a tissue is a fuzzy measure of the pace of cell replication versus pace of production of new cells by the stem cells that support that tissue. Stem cell activity declines with age, ergo so does average telomere length. The hypothesized risk lies in extending the life span of cells that are potentially cancerous. In mice, telomerase gene therapy is quite beneficial, both extending life and reducing cancer risk. Humans and other large mammals exhibit very different telomere dynamics, however, so one can't assume that the mouse data is a clear green signal. Given a company working towards this goal, we might hope that questions will be answered in the years ahead.
Longevity biotech Rejuvenation Technologies has emerged from stealth with seed financing to develop mRNA-based therapeutics to address mechanisms of aging. The company says it has developed an mRNA approach "capable of rewinding 10 years of telomere shortening with a single dose." Rejuvenation's products are optimized telomerase mRNA encapsulated in a custom tissue targeted lipid nanoparticle. The company says it plans to expand its operations and bring on additional team members to oversee scale-up manufacturing, clinical operations, and R&D efforts to expand mRNA delivery capabilities to additional organ systems.
"A single dose of our telomerase mRNA reverses years of telomere shortening in hours. Rejuvenation's LNP technology can also deliver mRNA to the lung and liver, and we've shown remarkable efficacy in preclinical models in both liver fibrosis and liver failure."
The Damage Done by Non-Standard Scientific Controls
To say that there is a lack of standardization in aging research is understating the matter. Pity the authors of reviews and meta-reviews, as they struggle to compare outcomes of animal studies between completely different, incompatible methodologies. Inconsistency in results is something of a feature even when different research groups attempt replication. The authors of this paper-length complaint focus down on one specific issue, the lack of standarization in the scientific control arm of a life span study, which is enough in and of itself to make comparison and replication challenging.
The search for interventions to slow down and even reverse aging is a burgeoning field. The literature cites hundreds of supposedly beneficial pharmacological and genetic interventions in model organisms: mice, rats, flies and worms, where research into physiology is routinely accompanied by lifespan data. Naturally the negative results are more frequent, yet scientifically quite valuable if analyzed systematically. Yet, there is a strong "discovery bias", i.e. results of interventions which turn out not to be beneficial remain unpublished.
Theoretically, all lifespan data is ripe for re-analysis: we could contrast the molecular targets and pathways across studies and help focus the further search for interventions. Alas, the results of most longevity studies are difficult to compare. This is in part because there are no clear, universally accepted standards for conducting such experiments or even for reporting such data. The situation is worsened by the fact that the authors often do not describe experimental conditions completely. As a result, works on longevity make up a set of precedents, each of which might be interesting in its own right, yet incoherent and incomparable. Here we point out specific issues and propose solutions for quality control by checking both inter-study and intra-study consistency of lifespan data.
Benefits of Calorie Restriction on Pancreatic Beta Cells
Researchers have studied calorie restriction as a means to slow aging quite extensively, but organisms are highly complex and there is always more that can be investigated. Here, researchers look in detail at the effects of calorie restriction in mice on the beta cells of the pancreas, necessary for the normal function of insulin metabolism. It is interesting to see mitophagy reduction as a means of increased mitochondrial function, though this could indicate that calorie restriction adjusts mitochondrial activity in ways that extend the functional life span of an individual mitochondrion, thereby less need for mitophagy. The big question regarding research into the mechanisms of calorie restriction is whether this is a useful way to find a basis for drug development aimed at slowing aging, given that long-lived species exhibit a much smaller effect on life span resulting from the practice of calorie restriction, and studies in mice almost certainly overstate benefits that might be obtained in humans.
Caloric restriction (CR) extends organismal lifespan and health span by improving glucose homeostasis mechanisms. How CR affects organellar structure and function of pancreatic beta cells over the lifetime of the animal remains unknown. We investigated these questions by exposing adult mice to mild CR (i.e., 20% restriction) for up to 12 months and applied in vivo and in vitro metabolic phenotyping of beta cell function followed by single cell multiomics and multi-modal high resolution microscopy pipelines (electron, light, mass spectrometry, and isotope microscopy) to investigate how CR modulates beta cell heterogeneity and longevity.
Gene regulatory network analysis links this transcriptional phenotype to transcription factors involved in beta cell identity (Mafa) and homeostasis (Atf6). Imaging metabolomics further demonstrates that CR beta cells are more energetically competent. In fact, high-resolution light and electron microscopy indicates that CR reduces beta cell mitophagy and increases mitochondria mass, increasing mitochondrial ATP generation. Finally, we show that long-term CR delays the onset of beta cell aging and senescence to promote longevity by reducing beta cell turnover. Therefore, CR could be a feasible approach to preserve compromised beta cells during aging and diabetes.
Reviewing Evidence for Urolithin A Supplementation
Mitochondria are the power plants of the cell, responsible for generating chemical energy store molecules to power cell processes. Urolithin A is one of a number of supplements shown to improve mitochondrial function, though as for the others it isn't all that impressive when compared to the effects of regular exercise. Nonetheless, this and other approaches to modestly attenuate age-related declines in mitochondrial function are under active development. They are not solutions to the problem of mitochondrial aging, however. For that we must look to more radical approaches to therapy, such as mitochondrial transplantation, allotopic expression of mitochondrial DNA in the cell nucleus, and partial reprogramming to reset expression of genes essential to mitochondrial function.
The aging of an organism is hallmarked by systemic loss of functional tissue, resulting in increased fragility and eventual development of age-related neurodegenerative, musculoskeletal, cardiovascular, and neoplastic diseases. Growing scientific evidence points to mitochondrial dysfunction as a key contributor in the aging process and subsequent development of age-related pathologies. Under normal physiologic conditions, the body removes dysfunctional mitochondria via an autophagic process known as mitophagy. Urolithin A (UA), a metabolite produced when gut microflora digests the polyphenol compounds ellagitannin and ellagic acid, is a known inducer of mitophagy via several identified mechanisms of action.
The primary objective of this scoping review is to identify and summarize the clinical relevance of UA supplementation in the prevention of age-related pathology and diseases. A computer-assisted literature review was performed using PubMed and EMBASE for primary source research articles examining UA supplementation and aging-related pathologies. A total of 293 articles were initially identified from a database search, and 15 articles remained for inclusion in this review, based on predetermined criteria. Analysis of the 15 identified publications demonstrated that UA holds potential as a dietary intervention for slowing the progression of aging and preventing the development of age-related disease. This review also illustrates the potential role that mitochondrial health and inflammation play in the progression of age-related pathology. Identifying the clinical relevance of UA supplementation in the prevention of age-related pathology and diseases will help further the focus of research on treatments that may improve the longevity and quality of life in patients at risk for these comorbidities.
Inflammation in Early Alzheimer's Disease
Chronic inflammation is a feature of many age-related conditions, including neurodegenerative diseases such as Alzheimer's disease. Is inflammation secondary to protein aggregation and other features of aging that drive the development of neurodegenerative conditions, or is inflammation of primary importance in the onset of cognitive impairment and Alzheimer's disease? These are complex conditions in which many forms of pathology and damage interact, and only now are there means to selectively reduce age-related chronic inflammation via the selective destruction of senescent cells. The results of clinical trials of therapies that clear senescent cells should provide some insight into the importance of inflammation in neurogenerative conditions.
Mild cognitive impairment (MCI) is characterized by an abnormal decline in mental and cognitive function compared with normal cognitive aging. It is an underlying condition of Alzheimer's disease (AD), an irreversible neurodegenerative disease. In recent years, neuroinflammation has been investigated as a new leading target that contributes to MCI progression into AD.
In the present study, we assessed a set of various serum and cerebrospinal fluid (CSF) biomarkers, including AD hallmarks and central nervous system and peripheral system inflammatory mediators, in a cohort of 30 healthy control, 45 non-impaired control, and 30 mild cognitively impaired patients. Our results confirmed specific activation of inflammatory processes in the brain of the MCI cohort. Additionally, the presence of systemic biomarkers in the CSF of the MCI population could give an indication of blood-brain barrier (BBB) permeability. Finally, IL-1β was upregulated in MCI serum and correlated with NLRP3 activation biomarkers.
AD has been described as a cascade of several biochemical mechanisms. First, the amyloid plaques start to accumulate abnormally in the brain, triggering an inflammatory response that will chronically exacerbate amyloid deposition and neurotoxicity. This will be followed by the production and hyperphosphorylation of tau proteins generating neurofibrillary tangles. All three mechanisms together are then responsible for altering neuronal transmission in the brain, which results in cognitive decline. Consequently, it is the combination of amyloids, inflammation, and tau proteins together that is responsible for cognitive impairment. As our patients have MCI based on cognitive tests and potentially early AD onset, the stage of the disease could correspond to the transition between amyloid aggregation and inflammatory response activation.
The Open Genes Database of Associations with Aging and Longevity
The Open Genes database provides summaries of the information available on longevity-associated genes, from well-established and well-replicated effects such as that associated with klotho expression, to much less well supported data. Thousands of genes have at least a study or two suggesting an effect on longevity in studies of lower animals, and many of those may turn out to be experimental error. Yet since every fundamental cellular process can be influenced by dozens or hundreds of genes, even though there are comparatively few important processes of aging, one might well expect there be to be thousands of related genes. Looking at the practical outcome of all of this study, at the end of the day, the large human epidemiological databases and genetic studies suggest that common gene variants have very little effect on longevity when compared to the impact of lifestyle choices. Genetics, I suspect, is not the road to human rejuvenation. Instead, therapies that repair specific forms of damage will be needed.
The Open Genes database was created to enhance and simplify the search for potential aging therapy targets. We collected data on 2402 genes associated with aging and developed convenient tools for searching and comparing gene features. A comprehensive description of genes has been provided, including lifespan-extending interventions, age-related changes, longevity associations, gene evolution, associations with diseases and hallmarks of aging, and functions of gene products.
For each experiment, we presented the necessary structured data for evaluating the experiment's quality and interpreting the study's findings. Our goal was to stay objective and precise while connecting a particular gene to human aging. We distinguished six types of studies and 12 criteria for adding genes to our database. Genes were classified according to the confidence level of the link between the gene and aging. All the data collected in a database are provided both by an API and a user interface. The database is publicly available on a website at https://open-genes.org/.