Fight Aging! Newsletter, February 27th 2023
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/
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- Endothelial Progenitor Cell Senescence as a Contributing Cause of Declining Angiogenesis
- Towards Ferrous Iron-Activated Senolytic Prodrugs to Clear Senescent Cells
- More Visible Examples of Progress in the Longevity Biotech Industry in 2022
- How Important is the Error Rate in Protein Synthesis to the Pace of Aging?
- Greater Thymic Atrophy Correlates with More Rapid Progression of Chronic Kidney Disease
- Alzheimer's Disease as a Consequence of Maladaptive Fructose Metabolism
- That Centenarians are Healthier is Unsurprising
- Thoughts on How to Help Advance Work on the Treatment of Aging
- Alternative Approaches to the Treatment of Mitochondrial Aging at the SENS Research Foundation
- A Discussion of Mitochondrially Derived Peptide MOTS-c
- Insufficient Water Intake May Correlate with Increased Arterial Stiffness
- Angiotensin-(1-7) Reverses Age-Related Increase in Myelopoiesis
- More on the Amyloid Cascade Hypothesis 2.0
- Hydrogen Sulfide and Mechanisms of Aging
- Centenarians Exhibit Better Protein Quality Control
Endothelial Progenitor Cell Senescence as a Contributing Cause of Declining Angiogenesis
Angiogenesis is the process of building new blood vessels in response to circumstances, such as a relative lack of oxygenation in tissues, or repair of injury. It is quite complicated, involving several distinct stages and the interactions of a variety of different cell populations. Angiogenesis declines with age, particularly in the context of maintaining capillaries. The density of capillary networks is reduced with age, and this may be quite influential in the aging of energy-hungry issues such as the brain and muscles. It isn't just a reduction in delivery of nutrients and oxygen. Loss of microvascular blood flow through tissues is likely also disruptive to the regulation of blood pressure, a factor contributing to the development of hypertension.
Which of the mechanisms of aging contribute to the loss of angiogenesis with age? Endothelial progenitor cells are one of the cell populations involved in angiogensis. In today's open access paper, the authors discuss cellular senescence in this population, and its negative effects on the capacity for angiogenesis, through the lens of microRNA regulation of these processes. Senescent cells grow in number with advancing age, in cell populations throughout the body. Their presence alters the cellular environment for the worse, generating inflammation and altered cell behavior. The research here provides just one example of many.
Hsa-miR-409-3p regulates endothelial progenitor senescence via PP2A-P38 and is a potential ageing marker in humans
Endothelial progenitor cells (EPCs), obtained from peripheral blood and identified as CD34 antigen-positive (CD34+) mononuclear cells, were marrow-derived stem cells and can differentiate into endothelial cells to promote neovascularisation in response to ischemic injury. Cell therapy using EPCs has been shown beneficial in ischaemia-related cardiovascular diseases (CVD) and emerged as useful substrates for neovascularization. However, some limitations make their clinical application difficult, such as heterogeneity in progenitor cell types, lack of standardization of specific surface markers and reduced number during ageing. Nonetheless, the angiogenic potential of EPCs has been an important target in regenerative medicine.
Numerous studies indicated that microRNA (miR or miRNA) is involved in post-transcriptional regulation of gene expression concerning diverse biological functions, including ageing and angiogenesis. A previous report showed that angiogenesis and tissue repair were regulated by miRNA-135a-3p via targeting p38 signalling in endothelial cells, revealing a link among miRNA, angiogenesis, and endothelial cells. In addition, increased miRNA-183-5p with age was involved in stem cell senescence. Furthermore, several studies have also addressed the regulation of miRNA during culture-induced senescence of vascular cells or in tissues.
These findings suggested that senescence and miRNAs may play an integrated role in modulating the pathologic processes of human CVD via the regulation of progenitor cell activity. We, therefore, in the present study explored the roles of hsa-microRNA (miR)-409-3p in senescence and signalling mechanism of human endothelial progenitor cells (EPCs). Hsa-miR-409-3p was found upregulated in senescent EPCs. Overexpression of miRNA mimics in young EPCs inhibited angiogenesis. In senescent EPCs, compared to young EPCs, protein phosphatase 2A (PP2A) was downregulated, with activation of p38/JNK by phosphorylation. Young EPCs treated with PP2A siRNA caused inhibited angiogenesis with activation of p38/JNK, similar to findings in senescent EPCs.
Inhibited angiogenesis of young EPCs after miRNA-409-3p mimics treatment was reversed by the p38 inhibitor. The effect of hsa-miR-409-3p on PP2A signalling was attenuated by exogenous VEGF. Analysis of human peripheral blood mononuclear cells (PBMCs) obtained from healthy people revealed hsa-miR-409-3p expression was higher in those older than 65 years, compared to those younger than 30 years, regardless of gender. In summary, hsa-miR-409-3p was upregulated in senescent EPCs and acted as a negative modulator of angiogenesis by regulating PP2A/p38 signalling.
Towards Ferrous Iron-Activated Senolytic Prodrugs to Clear Senescent Cells
Senescent cells accumulate with age throughout the body, and cause considerable disruption to tissue structure and function via their pro-inflammatory secretions. Clearing senescent cells is an important approach to rejuvenation and reversal of age-related disease, based on the impressive results produced in mice to date. One of the challenges inherent in the destruction of senescent cells is the variation shown in their biochemistry, depending on how they become senescent and on which tissue they reside in. Different treatments exhibit widely varying outcomes for different varieties of senescent cell, and those varieties are far from fully or comprehensively catalogued.
In today's open access paper, researchers describe a novel approach to the selective destruction of senescent cells, focusing on characteristics of the dysfunctional iron metabolism exhibited by cells that become senescent in response to the signaling of other senescent cells, undergoing what is know as paracrine senescence. The researchers show that should be possible to produce an iron-activated prodrug, in which the active cell-killing drug substance is masked by a chemical addition that is only stripped in cells that exhibit the aberrant iron metabolism characteristic of senescent cells. It is worth noting that prodrugs based on the high levels of β-galactosidase in senescent cells have shown considerable promise to date, so we might expect analogous approaches to be similarly interesting.
Selective ablation of primary and paracrine senescent cells by targeting iron dyshomeostasis
The molecular biology of cellular senescence has opened the possibility of exploiting the differential vulnerabilities of senescent cells (SCs) compared with healthy cells for the development of a new class of longevity therapeutics against aging and age-related disorders. However, the significant heterogeneity among SCs based on cell type of origin or senescence induction method suggests the need to develop senolytics that either have a broader therapeutic efficacy or that can target recalcitrant SCs.
In this context, paracrine senescence (PS) is the least understood type of senescence. Even though there have been previous efforts to characterize PSs, the fact that only a subset of cells exposed to the senescence-associated secretory phenotype (SASP) factors become senescent means that previous experimental protocols were compromised, with mixed cell populations dominated by non-senescent cells labeled as PSs. We were able to circumvent this major methodological issue by isolating and enriching PSs using the previously characterized SC surface marker DPP4.
We discovered that DPP4+ paracrine SCs (PSDPP4+) engage prosurvival pathways that are distinct from those on which DPP4+ primary SCs (SDPP4+) rely and are also relatively resistant to killing by senolytic drugs previously identified to be effective against primary SCs. Given that SCs accumulate ferrous iron (Fe(II), also known as labile iron), we sought to test a Fe(II)-targeting strategy in which Fenton reaction of a prodrug was coupled to release of drug payload. Others previously showed that the tumor-activated prodrug TRX-CBI (comprising a trioxolane-based [TRX] sensor of Fe(II) conjugated to a cytotoxic cyclopropylbenzindoline [CBI] payload) demonstrated selective toxicity in Fe(II)-rich cancer cells.
Here, we used a form of TRX-CBI to target cytotoxic CBI to SCs. We demonstrated that treatment with TRX-CBI triggers significant senolysis of both PSDPP4+ and SDPP4+, with negligible cytotoxicity toward non-senescent cells. Based on our results, we propose Fe(II)-based targeting of SCs with ferroptosis inducers or iron-activated drug conjugates as broad-spectrum senolytic agents.
More Visible Examples of Progress in the Longevity Biotech Industry in 2022
Much of the progress that takes place year after year in any segment of the broader biotech industry is invisible, and the growing portion of that industry focused on aging and longevity is no exception. Biotech is not a high profile industry, particularly because of the heavy dependence on intellectual property and trade secrets as a basis for government-granted monopolies on particular treatments. Details are kept quiet least larger entities in the industry to decide replicate a therapy and call it their own, because the potential rewards are worth the near certainty of a lawsuit. Thus every visible presentation or press release typically discusses only the very top of a near entirely buried edifice of hard work and research.
Today I'll point out a look back at the more visible news from 2022 in the industry, put together by one of the newer longevity-industry-focused venture funds, quadraScope. I help out by advising the fund principals, one of whom is an investor in the company I co-founded with Bill Cherman, Repair Biotechnologies. One example of the web of connections that ties the community together. The longevity industry and its investors is a growing but still comparative small community, and building networks of collaboration and connection is an essential part of that progress.
Longevity biotech progress in 2022
Despite the economic challenges of 2022, the emerging longevity biotech industry made impressive progress on several fronts, including positive results in clinical trials of senolytics and mitochondrial replacement therapies. Unity Biotechnology, backed by billionaires Jeff Bezos and Peter Thiel, reported positive results from a multicenter randomized clinical trial of a new senolytic drug to treat diabetic macular edema, a common cause of blindness in diabetic patients. Several companies, including Deciduous Therapeutics, Oisin Biotechnologies, and Cleara Biotech, are developing senolytic therapies to treat debilitating chronic conditions such as pulmonary fibrosis, diabetes, and cancer.
Mitochondrial replacement to restore cellular energy production is expected to be highly impactful for age reversal. Minovia, an Israeli biotech company, demonstrated the feasibility of transplanting mitochondria into humans. Although Minovia is treating an illness, their achievement suggests that a similar treatment could be used to enhance healthspan. In Minovia's clinical trial, children with single large-scale mitochondrial DNA deletion syndromes, a class of severe congenital mitochondrial diseases, received healthy mitochondria from their mothers. The benefits of the therapy were still evident one year after the transplant. Multiple startups are working on treatments to restore or replace aging mitochondria, including Mitrix Bio, Cellvie, Stealth BioTherapeutics, and Yuva Biosciences.
If proven feasible, cellular reprogramming could restore cell health and resilience, and treat diseases and disabilities caused by aging. 2021 and 2022 were the setup years for reprogramming with billions in funding and several ventures started. Ventures working on reprogramming include Altos Labs, NewLimit, Calico, Life Biosciences, Rejuvenate Bio, and Turn Biotechnologies. Altos Labs scientist Dr. Reik developed a method to reprogram cells, reversing their biological age by 30 years. Another Altos Labs scientist, Dr. Izpisua Belmonte, showed that long-term reprogramming was safe and could reverse age-related organ damage in mice. His group also developed an RNA-based therapy to reverse biological age and reduce inflammation in mice.
How Important is the Error Rate in Protein Synthesis to the Pace of Aging?
Cellular biochemistry is a messy process, a soup of colliding molecules moving at high speed and reacting with one another. Within this soup, complex processes of assembly and interaction take place. The blueprints of genes in DNA are converted into RNA via one complicated set of reading and assembly mechanisms in the cell nucleus. That RNA exits the nucleus and is then processed in ribosomes to produce proteins from amino acid fragments. Proteins are then folded in to the correct shape in the endoplasmic reticulum, and then must further be transported to a final destination within the cell.
All of this takes place within a dense storm of fast-moving molecules of all sorts, and any number of inappropriate interactions and reactions. Quality control is important, as all of the processes mentioned above can fail. Errant proteins and damaged structures are promptly identified and removed, broken down into amino acid fragments for recycling. Evolution has produced a system of assembly and quality control that has a high fidelity, suggesting that it is important for cell and tissue function for protein manufacture to produce few errors. But are variations in error rate an important contribution to differences in life span between species?
Thermophiles reveal the clues to longevity: precise protein synthesis
During the lifetime of an organism, proteins are constantly exposed to stressors that impair their function. Protein homeostasis networks have evolved to monitor and regulate the synthesis, folding, trafficking, and degradation of proteins. The earliest process in the protein life cycle that modulates cellular proteostasis is translation. Changes in levels or mutations in the components of translational machinery have a significant impact on longevity in several animals. For instance, mutation or depletion of ribosomal proteins and translation factors extend lifespan in yeast worms and flies. Similarly, blocking the mTOR (mammalian Target of Rapamycin) system through rapamycin reduces protein synthesis and increases lifespan. While the significance of protein synthesis in the aging process is widely accepted, it is unclear whether errors in protein synthesis or translational fidelity may play a part in aging per se.
Protein synthesis error rates in bacterial systems are estimated to be as high as 1 in 10^3 per amino acid. According to this estimation, up to 15%-20% of the cellular protein pool may contain mistranslation errors. Mistranslated proteins may not have a significant impact on cellular proteostasis at a young age, due in part to the quick turnover and efficient clearance of cellular proteins. However, in the older animal, protein turnover rates, proteasome activity, and autophagy decline, making them more sensitive to error-prone protein translation. Therefore, mistakes in protein translation have the potential to cause a variety of age-related diseases. So far, however, it was unclear whether accurate translation can affect cellular aging and if the rate and extent of mistranslation increase with aging.
Researchers recently proposed a mechanism of aging that is highly dependent on translational accuracy. The authors study ribosomal protein RPS23, a homolog of prokaryotic S12 protein that is conserved in all three domains of life, and implicate it in the maintenance of protein translational accuracy. The ribosomal protein S12 (eukaryotic homolog RPS23) contributes to translation accuracy. A single amino acid alteration in a ribosomal protein present in archaea can improve metazoan translation fidelity and survival. The authors conducted a comprehensive phylogenetic analysis of RPS23 and discovered that a lysine residue at position 60 is evolutionarily conserved, except in hyperthermophilic archaea, where arginine replaces it (RPS23-K60R).
CRISPR gene editing was used to insert a mutation into the Drosophila melanogaster Rps23 gene, which led to the substitution of the lysine 60 with an arginine residue. The translational accuracy of mutant and wild-type flies was determined with a reporter construct that contained a renilla luciferase gene followed by a firefly luciferase gene separated by an in-frame linker sequence containing a stop codon. Inclusion of a stop codon produces firefly only if a read-through error had occurred, and thus served as a measure of translational accuracy. It was discovered that the K60R mutation in the RPS23 protein decreased the frequency of mistakes made during protein synthesis, thereby leading to a reduction in firefly luciferase production in the mutants. Specifically, the stop-codon read-through increased considerably with aging in the control flies, but not in the RPS23-K60R mutant. Similar results were obtained in Caenorhabditis elegans and Schizosaccharomyces pombe (yeast), where the expression of the RPS23-K60R protein also reduced stop-codon read-through.
Given that the variant (RPS23 K60R) was initially discovered in hyperthermophilic archaea, the authors contended that the protein should provide an evolutionarily conserved mechanism of heat tolerance. Indeed, flies, worms, and yeast expressing RPS23-K60R protein were able to grow and survive at temperatures above the optimum. Finally, the physiological benefit of this mutation was demonstrated by an increase in healthy lifespan. The authors demonstrate that when the mutation was introduced, it improved lifespan by 9%-23% in all three model organisms. Additionally, the authors extend their findings by noting that treatments that prolong lifespan (such as rapamycin) do so by enhancing translational fidelity in controls but not in mutant K60R strains. Thus, they concluded that the primary determinant of the aging process was a reduction in translational fidelity.
Greater Thymic Atrophy Correlates with More Rapid Progression of Chronic Kidney Disease
It is the nature of becoming older that diverse and quite different age-related conditions proceed in parallel, linked by the contributions of shared underlying mechanisms, such as chronic inflammation, or mitochondrial dysfunction. Individuals age at different rates, largely the result of lifestyle choices and environmental factor such as exposure to persistent pathogens such as herpesviruses. In any given individual, however, different aspects of aging often appear correlated, as they are the results of deeper processes of damage and dysfunction.
The thymus is a small organ in which thymocytes produced in the bone marrow mature into T cells of the adaptive immune system. Active thymic tissue is slowly replaced with fat over later life, and the declining production of new T cells contributes to the age-related dysfunction of an immune system consisting ever more of worn, exhausted, malfunctioning, and senescent cells. Chronic kidney disease is most often a downstream consequence of diabetes and/or raised blood pressure, but rising numbers of senescent cells in older individuals are implicated in the fine details of its pathology, such as fibrosis, the production of scar-like excess collagen deposition that is disruptive of tissue structure and function.
Consider a correlation between the degree of thymic involution and the severity and progression of chronic kidney disease. These are very different issues, but both impacted by mechanisms such as the chronic inflammatory signaling characteristic of old age. In today's open access paper, researchers present data illustrating this correlation in a study population with chronic kidney disease. Correlation doesn't necessarily imply any direction of causation; both issues might contribute to the other, or be more independent outcomes of shared underlying mechanisms. The researchers here favor the idea that immune dysfunction contributes to a worsened progression of chronic kidney disease, however.
Decreased thymic output predicts progression of chronic kidney disease
In this study, we explored the impact of T cell senescence on the renal prognosis and mortality of patients with chronic kidney disease (CKD). We found that decreased recent thymic emigrant (RTE) T cells, which corresponds to decreased thymic output, was associated with CKD progression and high mortality, and an increase in highly differentiated CD28-CD4+ T cells, which increases with age, tended to be associated with CKD progression. Thymic atrophy is a characteristic of an aging immune system and has been implicated in age-related diseases such as infection, malignancy, atherosclerosis, and CKD. However, epidemiologic data are limited in patients with non-dialysis-dependent CKD. To our knowledge, this is the first study to demonstrate the impact of decreased thymic output on renal prognosis and all-cause mortality in patients with non-dialysis-dependent CKD.
An immunological model has been constructed using epidemiological and immunological data to show that an age-related decrease in thymic output is associated with the development of infectious diseases and malignancies. Decreased RTE in renal transplant patients increases all-cause mortality. In dialysis patients, decreased RTE is associated with death caused by infection, and decreased naive T cell count due to thymic atrophy increase all-cause mortality. Furthermore, our results are consistent with previous findings showing that shorter telomeres in peripheral blood leukocytes worsen renal prognosis and mortality, because the decrease in naive T cell counts due to thymic atrophy is compensated by increased T cell division, thereby shortening telomeres.
There are three potential mechanisms by which decreased thymic output contributes to CKD progression and increased mortality. (a) Low thymic output reduces the diversity of TCR repertoire and may reduce the clearance of senescent cells by immune cells. (b) When the number of newly produced naive T cells decreases, homeostatic proliferation maintains the peripheral T cell count. However, homeostatic proliferation increases the percentage of dysfunctional memory-type T cells in mice. These T cells secrete inflammatory chemokines involved in chronic tissue inflammation, delay kidney tissue repair after acute kidney injury, and may be associated with CKD progression. (c) Thymic atrophy may reflect a systemic state of aging. As aging progresses, local and systemic inflammation induced by senescent-associated secretory phenotype (SASP) causes organ damage, which may cause thymic atrophy and decreases kidney function, and increase mortality. Conversely, the presence of CKD decreases thymic output, increasing the susceptibility to further progression of CKD and high mortality.
Alzheimer's Disease as a Consequence of Maladaptive Fructose Metabolism
Researchers here discuss the idea that Alzheimer's disease results from high sugar and glycemic carbohydrate intake. It is certainly possible that this mechanism contributes, but one has to ask why, if this was a dominant mechanism, is lifestyle much less correlated with Alzheimer's incidence than is the case for common metabolic diseases such as type 2 diabetes? One of the challenges all along with Alzheimer's is that it doesn't have a strong enough correlation with metabolic dysfunction and lifestyle choice to believe that it can be wholly, or even largely, a metabolic condition.
An important aspect of survival is to assure enough food, water, and oxygen. Here, we describe a recently discovered response that favors survival in times of scarcity, and it is initiated by either ingestion or production of fructose. Unlike glucose, which is a source for immediate energy needs, fructose metabolism results in an orchestrated response to encourage food and water intake, reduce resting metabolism, stimulate fat and glycogen accumulation, and induce insulin resistance as a means to reduce metabolism and preserve glucose supply for the brain. How this survival mechanism affects brain metabolism, which in a resting human amounts to 20% of the overall energy demand, is only beginning to be understood.
Here, we review and extend a previous hypothesis that this survival mechanism has a major role in the development of Alzheimer's disease and may account for many of the early features, including cerebral glucose hypometabolism, mitochondrial dysfunction, and neuroinflammation. We propose that the pathway can be engaged in multiple ways, including diets high in sugar, high glycemic carbohydrates, and salt. In summary, we propose that Alzheimer's disease may be the consequence of a maladaptation to an evolutionary-based survival pathway and what had served to enhance survival acutely becomes injurious when engaged for extensive periods. Although more studies are needed on the role of fructose metabolism and its metabolite, uric acid, in Alzheimer's disease, we suggest that both dietary and pharmacologic trials to reduce fructose exposure or block fructose metabolism should be performed to determine whether there is potential benefit in the prevention, management, or treatment of this disease.
That Centenarians are Healthier is Unsurprising
In order to live longer, one needs to be more healthy, less impacted by dysfunction and damage, suffer fewer outright age-related diseases. This is what one sees when assessing centenarians against the average of the oldest populations. Aging is damage, and age-related disease is the manifestation of that damage. Different people age at different rates, largely the consequence of lifestyle choice and environmental factors such as exposure to persistent pathogens. It is also possible that genetic variants become more important in very late life by providing greater resilience, but so far the weight of evidence leans more towards lifestyle choice and luck when it comes to the small number of individuals who do survive to a century of age.
Centenarians exhibit extreme longevity and have been postulated, by some researchers, as a model for healthy aging. The identification of the characteristics of centenarians might be useful to understand the process of human aging. In this retrospective study, we took advantage of demographic, clinical, biological, and functional data of deceased individuals between 2014 and 2020 taken from the Basque Health Service electronic health records data lake. Fifty characteristics derived from demographic, clinical, pharmaceutical, biological, and functional data were studied in the descriptive analysis and compared through differences in means tests. Twenty-seven of them were used to build machine learning models in the predictive analysis and their relevance for classifying centenarians was assessed.
Most centenarians were women and lived in nursing homes. Importantly, they developed fewer diseases, took fewer drugs, and required fewer medical attendances. They also showed better biological profiles, exhibiting lower levels of glucose, hemoglobin, glycosylated hemoglobin, and triglycerides in blood analysis compared with non-centenarians. In addition, machine learning analyses revealed the main characteristics of the profiles associated with centenarians' status as being women, having fewer consultations, having fewer diagnoses of neoplasms, and having lower levels of hemoglobin.
Thoughts on How to Help Advance Work on the Treatment of Aging
This article lists a variety of types of activity and project that might be undertaken to help to speed up the development of ways to treat aging as a medical condition. If you don't have a background in the life sciences, but nonetheless find human longevity a compelling topic, and would like to work in the field, what can you do? That is a good question, and often asked. There are many options that don't involve working as a scientist in a laboratory, though educating yourself about the science helps a great deal when it comes to picking the better options from the array of choices on the table.
Aging is a set of molecular and cellular processes that affects us all, but what if we could extend our healthy lifespan and live longer, healthier lives? This is the goal of the rapidly growing field of longevity. And after my last post about leaving my CTO job to work on longevity a lot of people have reached out asking what I'm working on actually? What I'm building for longevity? The short answer is... nothing. Yet. The long answer is... well, this post. I believe that anyone can work on anything they put their mind to if they are willing to put in the time and effort to learn the necessary skills. Whether it's research, funding, talent, media, practical longevity, aging therapeutics, or infrastructure, there are numerous opportunities to make a significant impact in this field.
6.96 billion was raised across 96 funding rounds in 2022. This may seem like a lot but it's actually nothing. Remember that Instagram was acquired for 1 billion. So trying to bring more funding to the longevity field is very much needed. Someone needs to help talented people transition into the field. And believe me, we need far, far more people working on longevity. Recruiting and community building are important. The narrative around longevity is changing towards a more strategic conservatism which is proving to have better adoption. But it's far away from reaching a mainstream level. We need more communicators designing and evolving new narratives for different people.
The first drug targeted to extend healthy lifespan by 10-20 years could be developed and commercialized this decade. Aging therapeutics usually means getting the science out of the lab. So most often than not, someone with biology background will try to start or join a startup around their expertise. But what about people who are not coming from academia? The reality is that it may take anything from 6 months to 1 year (maybe even more) of full dedication to gain enough context, map the gaps, understand low hanging fruits, understand which technologies are the most promising, and get in love with a strong hypothesis to join or build a startup around it. This is the hardest part: in an ocean of possibilities, which one to choose? Which one is the most interesting? What technology is the most promising? What are the low hanging fruits?
Alternative Approaches to the Treatment of Mitochondrial Aging at the SENS Research Foundation
The primary approach to the prevention and treatment of mitochondrial aging undertaken by the SENS Research Foundation is allotopic expression, putting backup copies of mitochondrial genes into the nuclear genome. This prevents mitochondrial DNA mutations from degrading mitochondrial function in ways that can become pathological. This isn't the only approach on the table, however, and here some of the others are outlined.
Mitochondrial mutations - and above all, large deletions in the mitochondrial DNA - accumulate in long-lived cells over our lifetime. And until we can do something to repair or bypass that problem, the overtaking of this small fraction of our cells by deletion-bearing mitochondria will continue to drive diseases of aging. Long before there was a SENS Research Foundation - even before a "Strategies for Engineered Negligible Senescence" (SENS) platform existed - our founding CSO Dr. Aubrey de Grey surveyed the possible solutions for this problem, and the only one that seemed viable was allotopic expression (AE).
So why - after making great leaps forward with the science - are we now breaking ground on entirely new MitoSENS strategies? A few reasons. Considered at the most fundamental level, AE itself is an inherently difficult biotechnological challenge. Then there's the additional hurdle of delivering it to those cells that are vulnerable to mitochondrial mutations with age. Thus scientists in our MitoSENS lab are now working on two of these alternative strategies - both of them also thought up or endorsed by Dr. de Grey. You might think of them as backup strategies for the backup copies.
One of these strategies is to use a form of mitochondrial transplantation to replace the cell's mutation-bearing mitochondria with healthy ones. For mitochondrial transplantation to work as a rejuvenation biotechnology, we need a way not only to get the transplanted mitochondria into the cells, but to enable them to bypass the selective advantage of the native mitochondria, and especially of the powerful advantage of mutation-bearing mitochondria. This is where the relatively new biotechnology of "gene drives" come in. Engineered mitochondria would use restriction enzymes designed to target one of the several restriction sites that are naturally present in the host's mitochondria. The restriction enzyme would quickly go to work eviscerating the cell's original mitochondrial DNA, thereby clearing space to allow the new, transplanted mitochondria to take over.
We can't say much about the second strategy the MitoSENS team is exploring because it's a very early-stage project, and we want to be sure we're on the right track before making any announcements. All we'll say for now is that our scientists have identified a drug that may potentially "unmask" deletion-bearing mitochondria, attracting the attention of the mitophagy machinery and allowing it to cull them. Under some circumstances, such "unmasking" is sufficient to keep deletion-bearing mitochondria at bay when they haven't yet overtaken the cell. If the drug we're testing (or a similar one) could do that, we might be able to keep many cells operating normally by holding deletion-bearing mitochondria down to a minority of the population, and keep other cells free of deletion-bearing mitochondria entirely by catching the first one and sending it to its grave.
A Discussion of Mitochondrially Derived Peptide MOTS-c
A number of mitochondrially derived peptides are thought to have positive effects on cell function, though as for most of the approaches of this nature, it is unclear that it is any better than a structured exercise program. One of the better studied of these peptides is MOTS-c, which is itself upregulated by exercise - arguably one of a number of known exercise mimetics. Delivering signal molecules that are normally upregulated by exercise should in principle recapture some of the beneficial effects of exercise, but so far this line of development has yet to much improve on exercise itself.
Mitochondria are organelles required for the production of ATP. A mitochondrion exhibits semi-autonomous genetic systems, independent genomes, and unique genetic codes that are similar to those found in bacteria. Recently, a short open reading frame (sORF) encoded in the mitochondrial genome has been discovered. These sORF produce bioactive peptides, collectively known as mitochondrial-derived peptides (MDP), which have a wide range of physiological functions and can explain how mitochondria communicate within and between cells in a specific disease environment. Mitochondrial-derived peptides may answer the key biological problems that have plagued the field for decades (such as mitochondrial-nuclear communication, metabolic dysfunction, etc.). Whether in the form of mitochondrial-derived peptide itself or in terms of sORF, mitochondrial-derived peptide is suitable for research as a therapeutic agent.
Mitochondrial-derived peptide called MOTS-c has been shown to significantly reduce the level of pro-inflammatory factors in mice and increase anti-inflammatory factors and insulin-stimulated glucose treatment rates, as well as glucose homeostasis. Furthermore, human studies showed that exercise increased MOTS-c levels in skeletal muscle and blood circulation, indicating that MOTS-c is a mitochondrial-derived peptide induced by skeletal muscle exercise. Additionally, studies have revealed the importance of MOTS-c in regulating obesity and diabetes, longevity, and cardiovascular disease. Specifically, this paper discusses the application of mitochondrial-derived peptides, including MOTS-c, in the treatment of diseases and anticipates the future development direction of MOTS-c combining synthetic biology to provide new ideas on how it can be developed and applied.
Insufficient Water Intake May Correlate with Increased Arterial Stiffness
As a companion piece to a recent discussion of whether mild dehydration is both quite prevalent and meaningfully impacts aspects of aging, one might look at this study of water consumption and vascular health in hyperuremic individuals. A relationship between lower water intake and arterial stiffness was only significant in women, but nonetheless it is interesting to see data that suggests at least some populations are harming themselves over the long term via too little water intake.
Hyperuricemia is defined as an elevated serum uric acid (sUA) level in the blood and is well-known as an independent risk factor for the development of hypertension, metabolic syndrome, and cardiovascular disease. Water is essential to most bodily functions, and its consumption rates appear to decline with age. The aim was to evaluate the influence of water intake on early vascular aging in metabolic middle-aged patients with hyperuricemia.
The study included 241 men aged 40-55 years and 420 women aged 50-65 years from the Lithuanian High Cardiovascular Risk (LitHiR) primary prevention program. Anthropometric characteristics, blood pressure, laboratory testing, and the specialized nutrition profile questionnaire were evaluated. Carotid-femoral pulse wave velocity (cfPWV), assessed using applanation tonometry, was evaluated as an early vascular aging parameter in patients with hyperuricemia and with normal sUA levels.
72.6% of men and 83.1% of women drink insufficient amounts of water (less than 1.5 L per day). However, our results showed statistically significant relationships only among a group of women. The women in the hyperuricemic group had a higher cfPWV than women with normal sUA levels. In hyperuricemic women, drinking less than 0.5 L per day in combination with other risk factors, such as age, increasing fasting glucose, and systolic blood pressure, was statistically significantly associated with an increased cfPWV.
Angiotensin-(1-7) Reverses Age-Related Increase in Myelopoiesis
One of the noteworthy aspects of immune aging is a growing bias towards the creation of myeloid cells (such as monocytes) at the expense of the creation of lymphoid cells (such as the thymocytes that mature into T cells) in the bone marrow. This changes the overall behavior of the immune system for the worse. Researchers here find that the peptide angiotensin-(1-7) can be used to reverse some of these changes in mice, which is an interesting finding.
Aging is associated with chronic systemic inflammation largely due to increased myelopoiesis, which in turn increases risk for vascular disease. We have previously shown evidence for the therapeutic potential of Angiotensin-(1-7) (Ang-(1-7)) in reversing vasoreparative dysfunction in aging. This study tested the hypothesis that ischemic vascular repair in aging by Ang-(1-7) involves attenuation of myelopoietic potential in the bone marrow and decreased mobilization of inflammatory cells.
Young or Old male mice of age 3-4 and 22-24 months, respectively, received Ang-(1-7) for four weeks. Myelopoiesis was evaluated in the bone marrow (BM) cells by carrying out the colony forming unit (CFU-GM) assay followed by flow cytometry of monocyte-macrophages. Expression of pro-myelopoietic factors and alarmins in the hematopoietic progenitor-enriched BM cells was evaluated. Hindlimb ischemia (HLI) was induced by femoral ligation, and mobilization of monocytes into the blood stream was determined. Blood flow recovery was monitored and infiltration of inflammatory cells was evaluated by immunohistochemistry.
BM cells from Old mice generated a higher number of monocytes and M1 macrophages compared to that of Young, which was reversed by Ang-(1-7). Gene expression of selected myelopoietic factors, alarmins, and the receptor for alarmins, RAGE, was higher in the Old hematopoietic progenitor-enriched BM cells compared to the Young. Increased expressions of these factors were decreased by Ang-(1-7). Ischemia-induced mobilization of monocytes was higher in Old mice with decreased blood flow recovery and increased infiltration of monocyte-macrophages compared to the Young, all of which were reversed by Ang-(1-7). Enhanced ischemic vascular repair by Ang-(1-7) in aging is largely by decreasing the generation and recruitment of inflammatory monocyte-macrophages to the areas of ischemic injury. This is associated with decreased alarmin signaling in the BM-hematopoietic progenitor cells.
More on the Amyloid Cascade Hypothesis 2.0
Researchers recently proposed a version 2.0 of the amyloid cascade hypothesis regarding the development of Alzheimer's disease. This was provoked by the failure of amyloid-clearing immunotherapies to produce meaningful benefits in patients. Those results require rethinking the role of amyloid-β in Alzheimer's disease. Some researchers theorize that amyloid-β aggregation is a side-effect of the real disease process, which is more a matter of persistent viral infection and consequent chronic inflammation in brain tissue. The amyloid hypothesis 2.0 keeps amyloid-β front and center as the primary early stage disease mechanism, however. The question is whether the right type or localization of amyloid-β is being targeted by current research programs: almost certainly not, given the poor results to date.
Recently, we proposed the Amyloid Cascade Hypothesis 2.0 (ACH2.0), a reformulation of the original Amyloid Cascade Hypothesis (ACH). In ACH2.0, in contrast to ACH, Alzheimer's disease (AD) is driven by intraneuronal amyloid-β (iAβ) rather than extraneuronal amyloid-β and occurs in two stages. In the first, relatively benign stage, Aβ protein precursor (AβPP)-derived iAβ activates. Then upon reaching a critical threshold, the AβPP-independent iAβ-generating pathway triggers a devastating second stage resulting in neuronal death.
While the ACH2.0 remains aligned with the ACH premise that Aβ is toxic, the toxicity is exerted because of intracellular rather than extracellular Aβ. In this framework, a once-in-a-lifetime-only iAβ depletion treatment via transient activation of BACE1 and/or BACE2 (exploiting their Aβ-cleaving activities) or by any means appears to be the best therapeutic strategy for AD.
Whereas the notion of differentially derived iAβ being the principal moving force at both AD stages is both plausible and elegant, a possibility remains that the second AD stage is enabled by an AβPP-derived iAβ-activated self-sustaining mechanism producing a yet undefined deleterious "substance X" which anchors the second AD stage. The present study generalizes the ACH2.0 by incorporating this possibility and shows that, in this scenario, the iAβ depletion therapy may be ineffective at symptomatic AD stages but fully retains its preventive potential for both AD and the aging-associated cognitive decline, which is defined in the ACH2.0 framework as the extended first stage of AD.
Hydrogen Sulfide and Mechanisms of Aging
Researchers here discuss an investigation of the role of hydrogen sulfide in cell function and long-term health. Upregulation of hydrogen sulfide levels is an approach to modifying metabolism in order to modestly slow aging, and researchers here note an overlap with the mechanisms of calorie restriction, in that low nutrient levels increase the production of hydrogen sulfide in the body. While scientifically interesting, this sort of intervention is hardly the way forward to meaningfully extend the healthy human life span. We need better, more targeted approaches that do more to directly reverse the damage and dysfunction of aged tissues.
The molecular determinants of lifespan can be examined in animal models with the long-term objective of applying what is learned to the development of strategies to enhance longevity in humans. Here, we comment on a recent publication examining the molecular mechanisms that determine lifespan in worms, Caenorhabditis elegans (C. elegans), where it was shown that inhibiting protein synthesis increased levels of the transcription factor, ATF4. Gene expression analyses showed that ATF4 increased the expression of genes responsible for the formation of the gas, hydrogen sulfide (H2S).
Further examination showed that H2S increased longevity in C. elegans by modifying proteins in ways that stabilize their structures and enhance their functions. H2S has been shown to improve cardiovascular performance in mouse models of heart disease, and clinical trials are underway to test the effects of H2S on cardiovascular health in humans. These findings support the concept that nutrient deprivation, which slows protein synthesis and leads to ATF4-mediated H2S production, may extend lifespan by improving the function of the cardiovascular system and other systems that influence longevity in humans.
Centenarians Exhibit Better Protein Quality Control
Researchers here note that a number of cellular quality control mechanisms exhibit better function in centenarians than in the average elderly population. It is thought that the various systems responsible for quality control of proteins, such as autophagy, decline in function with advancing age. Given this, it is perhaps to be expected that centenarians exhibit a slower reduction in this capacity than their peers. In order to become centenarians, these individuals must necessarily be less impacted by aging, less damaged, less dysfunctional.
We have shown before that at least one intracellular proteolytic system seems to be at least as abundant in the peripheral blood lymphocytes of centenarians as in the same cells of young individuals (with the cells of the elderly population showing a significant dip compared to both young and centenarian cohorts). Despite scarce published data, in this review, we tried to answer the question how do different types of cells of longevous people - nonagenarians to semi-supercentenarians - maintain the quality and quantity of their structural and functional proteins? Specifically, we asked if more robust proteodynamics participate in longevity.
We hypothesized that at least some factors controlling the maintenance of cellular proteomes in centenarians will remain at the "young" level (just performing better than in the average elderly). In our quest, we considered multiple aspects of cellular protein maintenance (proteodynamics), including the quality of transcribed DNA, its epigenetic changes, fidelity and quantitative features of transcription of both mRNA and noncoding RNAs, the process of translation, posttranslational modifications leading to maturation and functionalization of nascent proteins, and, finally, multiple facets of the process of elimination of misfolded, aggregated, and otherwise dysfunctional proteins (autophagy). We also included the status of mitochondria, especially production of ATP necessary for protein synthesis and maintenance.
We found that with the exception of the latter and of chaperone function, practically all of the considered aspects did show better performance in centenarians than in the average elderly, and most of them approached the levels/activities seen in the cells of young individuals.