Fight Aging! Newsletter, November 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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- Year End Fundraisers For Rejuvenation Research at SENS Research Foundation and LEV Foundation
- Further Evidence for Reduced Blood Pressure to Lower Risk of Dementia
- An Aging Clock Derived from Images of the Lens of the Eye
- Learning from Laron Syndrome
- A Novel Mitophagy Inducing Compound
- Restoring Lost Vascularization Capability via FDPS Inhibition
- Alzheimer's as an Axonal Damage Condition
- Some Cancers Induce Cellular Senescence to Aid in Growth
- A Therapy to Reduce Lipoprotein(a) Levels
- Semaglutide Use Reduces Heart Attack Incidence in Obese Individuals
- Assessing Pentadecanoic Acid In Vitro
- Senescent Cells in the Human Brain
- A Diminished State Space View of Cognitive Aging
- Bioprinting Skin with Hair Follicles
- USP30 Inhibition Stops Progression of Parkinson's Disease in Mice
Year End Fundraisers For Rejuvenation Research at SENS Research Foundation and LEV Foundation
https://www.fightaging.org/archives/2023/11/year-end-fundraisers-for-rejuvenation-research-at-sens-research-foundation-and-lev-foundation/
When it comes to treating aging as a medical condition, it is important to fund the right sort of research program. All too much of the field of translational aging research is focused on finding ways to produce small benefits, such as via the use of repurposed existing supplements. This may produce gains for investors, but it won't meaningfully change the present shape of a human life. We need to do better than that. Fortunately, there are a small number of non-profit organizations and academic groups focused on development of the means of rejuvenation, rather than on means of modestly slowing aging. Two of the best are the SENS Research Foundation and LEV Foundation, both informed by the Strategies for Engineered Negligible Senescence (SENS), a list of important contributing causes of aging, the cell and tissue damage that causes dysfunction, alongside proposed forms of therapy to repair that damage.
Both of these non-profit organizations are presently running year end fundraisers to support their ongoing research programs, covering important areas of aging and rejuvenation that are not receiving sufficient attention elsewhere in the research community, or that are slowed by challenges in the fundamental science, or that are neglected by researchers due to a lack of tooling or a foundation to proceed. I consider both the SENS Research Foundation and LEV Foundation to be worthy recipients for your charitable donations. If you want to see a future in which aging has become a treatable medical condition, then take action! Do something to help the groups that are trying to make that future a reality! Funding makes the world turn; progress in building the foundations for rejuvenation therapies depends upon those funds.
SENS Research Foundation: Welcome to our 2023 End of Year Campaign
SENS Research Foundation (SRF) has spent the past year diligently employing your generous contributions towards accelerating the development of therapies to prevent, treat, and cure the diseases of aging. Just this year we've spoken at longevity conferences, highlighted our work with US policy makers and global leaders in health, submitted patents and publications on our research, educated dozens of students, supported translational therapies in their journey to market, and so much more. This End of Year Campaign focuses on SRF and the relationships we have built over the last couple years. These collaborations grow the effectiveness of our community and industry, extending our reach and deepening our impact to target directly the diseases and disabilities of aging. Every week we highlight a new organization and the real-world impact they are making to turn our mission into reality.
LEV Foundation: 2023 End-of-Year Fundraiser
LEV Foundation's story has just begun. In 2024, with your support, we're planning to: (a) Initiate the second study in the Robust Mouse Rejuvenation program. Building on the success of the ongoing first experiment, RMR-2 will shed light on the interactions between a new panel of therapies. (b) Bring the Dublin Longevity Declaration's message of hope to a global audience, through a major media campaign including translations into most widely-spoken languages. We'll recruit more renowned signatories - and even more importantly, build on the foundation the Declaration has provided to engage with policymakers and leaders around the world, seeking concrete action on its fundamental recommendation: to immediately expand research on extending healthy human lifespans. (c) Organize and support the next Longevity Summit Dublin, scheduled to take place on June 13-16, 2024. Speakers will be announced over the coming months, but we're already very confident that the third edition of the Summit will be just as unmissable as the first two events. (d) Continue enabling our partners at the Healthspan Action Coalition, Alliance for Longevity Initiatives (A4LI), and AfroLongevity, to build stronger connections with established public- and private-sector organizations, enhancing awareness of the potential of longevity research amongst those who set priorities for healthcare and research funding at all levels. A4LI's goals for the coming year include establishing an annual legislative briefing for longevity science in the US House of Representatives, and promoting passage of the Advanced Approval Pathway for Longevity Medicines.
Further Evidence for Reduced Blood Pressure to Lower Risk of Dementia
https://www.fightaging.org/archives/2023/11/further-evidence-for-reduced-blood-pressure-to-lower-risk-of-dementia/
The raised blood pressure of hypertension causes a great deal of downstream damage. It is a way for low-level biochemical damage associated with aging to become actual physical damage to the body. Pressure damage can occur in delicate tissues throughout the body, and raised blood pressure increases the pace at which capillaries and other small vessels rupture. Further, increased blood pressure can accelerate the development of atherosclerosis, and also contributes to the pathological enlargement and weakening of heart muscle. All of this downstream harm is why forcing a reduction in blood pressure, without addressing any of the underlying cell and tissue damage that causes hypertension, can nonetheless produce benefits to long-term health. Antihypertensive medications do not in any way touch upon the biochemistry of aging, but rather act to force regulatory mechanisms of blood pressure into a certain state.
There is a great deal of epidemiological evidence to show that higher blood pressure correlates with increased mortality and risk dementia. There is also a good deal of evidence for control of blood pressure via hypertensive drugs to reduce mortality and risk of dementia. Today's notes on recent research add to this evidence, reporting on a recent study in China. In this context, it is worth noting that in recent years it has become clear that lower blood pressure is better even in the normal range, that reducing below the 120s mmHg systolic blood pressure that are the present target continues to produce benefits.
Lowering blood pressure significantly reduced dementia risk in people with hypertension
Researchers evaluated the effectiveness of lowering blood pressure on dementia risk among people with high blood pressure. The study was conducted in 326 villages in rural China and included approximately 34,000 adults, ages 40 and older, with untreated blood pressure of 140/90 mm Hg or higher, or 130/80 mm Hg or higher for people at high risk for cardiovascular disease or those currently taking blood pressure medication. Half of the villages were randomly assigned to a village doctor-led intensive blood pressure intervention strategy, and half of the villages were randomly assigned to usual care. Patients in the usual care villages received their hypertension management from local village doctors or primary care physicians at township hospitals as part of routine health service covered by the China New Rural Cooperative Medical Scheme (a health insurance plan covering approximately 99% of rural residents for basic health-care services in China).
In the intervention group, trained village doctors initiated and adjusted antihypertensive medications based on a straightforward treatment protocol to achieve a goal of lowering systolic blood pressure to less than 130 mm Hg and diastolic blood pressure to less than 80 mm Hg, with supervision from primary care physicians. The stepwise protocol for hypertension management included a treatment algorithm, selection of medication, review of contraindications of medications and, finally, strategies to adjust dose. They also provided discounted and free blood pressure medications to patients and conducted health coaching on lifestyle modifications, home blood-pressure measurement and medication adherence.
The analysis found that the people in the intervention group showed significant improvement in blood pressure control and reduced dementia and cognitive impairment, no dementia compared to those who received usual care. The average blood pressure in the intervention group at 48 months was 128/73 mm Hg, compared to 148/81 mm Hg in the usual care group. On average, systolic blood pressure decreased by 22 mm Hg and diastolic blood pressure decreased by 9 mm Hg among people in the intervention group compared to usual care. People in the intervention group had 15% lower risk of dementia and 16% lower risk of memory impairment compared to the group that received usual care. Serious adverse events, such as hospitalizations and death from all causes, were also less frequent in the intervention group.
An Aging Clock Derived from Images of the Lens of the Eye
https://www.fightaging.org/archives/2023/11/an-aging-clock-derived-from-images-of-the-lens-of-the-eye/
Recent years have made it clear that any sufficiently large set of data derived from biochemistry or physiology can be fed into a machine learning process to develop an weighted combination of measures that reflects biological age. These aging clocks have been derived from many forms of omics data, from frequently measured blood biomarkers, from various other combination of common measures of health. Interestingly, photography of the face and, separately, of retinal structure also provide enough data for the development of clocks. In today's open access paper, researchers report on a clock developed from photography of the lens of the eye.
All of these clocks are discovered, not designed. Thus once a given weighted combination of measures is in hand, the next, harder question is how exactly it relates to the underlying processes of aging. This is important because we want clocks that work well to assess the effects of novel interventions and potential interventions on the state of biological age. It we can't be certain that a clock will, say, accurately reflect the contribution of senescent cells to aging, then one can't trust that clock in testing the effects of senolytic therapies that clear senescent cells. One would have to calibrate the clocks against the therapy in life span studies, which somewhat defeats the point of having a clock in the first place. The development of sufficient data and understanding to circumvent this issue is the primary challenge in the ongoing development of aging clocks.
LensAge index as a deep learning-based biological age for self-monitoring the risks of age-related diseases and mortality
Assessing an individual's aging process is important to evaluate one's health status. As one ages, the human body becomes frail with regard to biological functions and the occurrence of chronic diseases, such as Alzheimer's disease, cancer, diabetes, and cardiovascular diseases. Chronological age is defined as the time that an individual has experienced since birth. Since aging involves complex determinants, including genetic regulation, and the nutritional and environmental factors, peers with the same chronological age vary in aging and may have different health status and life expectancy. Thus, chronological age does not precisely reveal the true physiological age of individuals.
Biological age assessment based on various physiological biomarkers can quantitatively evaluate the degree of aging and predict the mortality and incidence of age-related diseases more accurately than chronological age. However, measuring biological age is challenging, largely due to obstacles in sample collection, variable aging rates of different tissues, and insufficient reliability of measuring tools and protocols. Intensive investigations of the biological indicators reflecting the overall aging pace of the human body are currently underway. For example, invasive methods measuring telomere length and DNA methylation status, profiling transcriptomics and proteomics, and the inflammatory aging clock have been used to generate biomarkers of aging at the molecular level using human blood cells. Furthermore, noninvasive techniques using machine learning and medical imaging, such as chest X-ray, magnetic resonance imaging (MRI) of the brain, and 3D facial imaging, were introduced to evaluate biological aging. However, these techniques are limited by high costs or instability in clinical practice. Therefore, a more objective, reliable, convenient, and noninvasive method that can accurately evaluate the biological age of an individual has yet to be developed for broader applications and self-management of health status.
The human lens, located in the anterior segment of the eye, is transparent under normal conditions and exchanges substances with the vitreous through the aqueous humor cycle. Age-dependent changes in the lens include nucleus enlargement, elasticity reduction, and increased opacity, all of which can be objectively and reliably observed through noninvasive imaging and rapidly assessed using digital photography. Thus, the human lens appears to be an optimal tissue with unique advantages for assessing biological age.
In this study, we used informative lens photographs to generate LensAge as an innovative indicator to reveal aging status of lens based on deep learning (DL) models. Under ideal physiological conditions (both genetic and environmental), biological age should be synchronized with chronological age. While in reality, there are almost always differences between biological age and chronological age, which is considered to result from individually different aging processes. Therefore, we measured the difference between LensAge and chronological age as the LensAge index to assess an individual's aging rate relative to peers, and investigated its ability to evaluate the risks of age-related disease occurrence and all-cause mortality. Importantly, we tested whether our models can be generalized to smartphone-based lens photographs, which may have potential applications for self-monitoring the risks of age-related diseases and mortality during aging.
Learning from Laron Syndrome
https://www.fightaging.org/archives/2023/11/learning-from-laron-syndrome/
The longest lived mice are still those engineered to lack functional growth hormone or growth hormone receptor. That record was established more than 20 years ago, and remains in place even as an energetic research and development community focused on treating aging as a medical condition has come into being. In part this is the case because research has largely focused on approaches known to produce lesser effects on aging in mice, such as the discovery of small molecules that mimic portions of the calorie restriction response. In part it is because the pace of development in the life sciences is ever slower than we would like it to be.
There are human practitioners of calorie restriction, and clinical trials have been conducted. This is how we know that calorie restriction in mice, largely operating through upregulation of autophagy, produces much larger effects on life span than is the case in humans. In the same way, there are humans who lack functional growth hormone or growth hormone receptor, the largest population of which exhibit Laron syndrome. Preliminary studies suggest that Laron syndrome provides some protection against cancer and metabolic disease, but there is no indication of extended life spans. So again the effect is small in humans in comparison to large in mice.
The consensus view on why this is the case is that humans are already fairly optimized for longevity, at least within the mammalian paradigm for cell and tissue biochemistry, or the parts of it most affected by calorie restriction and growth hormone metabolism. Our evolutionary history has been one in which we departed from our fellow primates in intelligence and sociology, leading to selection pressure for longer lives due to the ability of elders to help their descendants achieve reproductive success. Still, what about the rest of our biology? One of the most interesting questions in the field of aging research is how therapies to slow or reverse aging will differ in their performance between mice and humans once we depart from manipulation of growth-related metabolism to instead target the causes of aging, such as via clearance of senescent cells.
Insulin-like growth factors and aging: lessons from Laron syndrome
Pituitary-derived growth hormone (GH) along with insulin-like growth factor-1 (IGF1) constitute an endocrine axis with critical roles in growth and development. IGF1 is evolutionarily and structurally related to insulin. IGF1 production continues to be dependent on hypophysial GH secretion throughout all stages of life. Aging is linked to various endocrine deficits. In the specific context of the somatotrophic axis, GH and IGF1 biosynthesis progressively decrease as we age due to reduced activity of the hypothalamic GH releasing hormone (GHRH)-GH neuroendocrine system. Thus, while maximal GH and IGF1 levels are reached at mid-puberty, concentrations around the eight decade of life become drastically reduced. Indeed, both the amplitude of the GH secretory pulses as well as the basal levels between pulses are largely decreased. Reduction of endocrine GH levels is closely followed by a parallel decline in circulating IGF1.
Evidence has accumulated in recent years demonstrating that disturbance of the GH-IGF1 network correlates with prolonged lifespan in a number of animal species, including flies (D. melanogaster), nematodes (C. elegans) and mouse (M. musculus). Male mice harboring a disrupted GH receptor (GHR) gene ('Laron' mice) survive 55% longer than wild-type animals whereas female Laron mice have a 38% longer lifespan. The cellular and biochemical mechanisms that are responsible for the association between abrogation of the GH-IGF1 axis and prolonged lifespan are complex. Briefly, these mechanisms are functionally linked to the physiological role played by these hormones in nutrient sensing. Of relevance, whereas the effect of individual mutations on lifespan and health span in humans is usually difficult to assess, genomic analyses identified several differentially-represented aging-associated genes in Laron syndrome (LS) patients.
Epidemiological analyses have shown that patients with LS, the best-characterized disease under the umbrella of the congenital IGF1 deficiencies, seem to be protected from cancer. While aging and cancer, as a rule, are considered diametrically opposite processes, modern lines of evidence reinforce the notion that aging and cancer might, as a matter of fact, be regarded as divergent manifestations of identical biochemical and cellular underlying processes. While the effect of individual mutations on lifespan and health span is very difficult to assess, genome-wide screenings identified a number of differentially represented aging- and longevity-associated genes in patients with LS. The present review summarizes recent data that emerged from comprehensive analyses of LS patients and portrays a number of previously unrecognized targets for GH-IGF1 action. Our article sheds light on complex aging and longevity processes, with a particular emphasis on the role of the GH-IGF1 network in these mechanisms.
A Novel Mitophagy Inducing Compound
https://www.fightaging.org/archives/2023/11/a-novel-mitophagy-inducing-compound/
A sizable fraction of research aimed at treating aging involves screening natural compounds in search of those that can modestly slow aging in short-lived animal models. This is because the economics of developing such a compound into a drug or supplement are well understood by investors, and because it dovetails well with the scientific goal of increased understanding of how aging progresses at the level of cellular biochemistry, rather than because it is going to make a big difference for patients. If sizable gains in healthy life span were the driving incentive, the field would look very different, and the emphasis would be on different approaches.
Today's publicity materials are a good example of the way in which unbiased screening works. It tends to find ways to influence the well-known set of mechanisms related to the calorie restriction response, responsible for the plasticity of life span in short-lived species. These include upregulation of autophagy, specific upregulation of mitophagy, the autophagic processes responsible for clearing damaged and worn mitochondria, improvement of mitochondrial function via other means, and so forth. The problem with adopting this approach is that calorie restriction and related alterations in metabolism produce much smaller gains in life expectancy in long-lived species than in the short-lived species used in screening. Thus unbiased screening as a basis for a program is more or less a guarantee of producing marginal therapies. We have to do better than this.
New drug-like molecule extends lifespan, ameliorates pathology in worms and boosts function in mammalian muscle cells
Defective mitophagy is implicated in many age-related diseases. It's tied to neurodegenerative disorders such as Parkinson's and Alzheimer's; it plays a role in cardiovascular diseases including heart failure; it influences metabolic disorders including obesity and type 2 diabetes; it is implicated in muscle wasting and sarcopenia and has a complex relationship with cancer progression. Even though interventions that restore mitophagy and facilitate the elimination of damaged mitochondria hold great promise for addressing these conditions, not one treatment has been approved for human use despite advances in the field.
MIC (Mitophagy-Inducing Compound) is a coumarin, which are naturally bioactive compounds that have anticoagulant, antibacterial, antifungal, antiviral, anticancer, and antihyperglycemic properties (among others) as well as being an antioxidant with neuroprotective effects. Coumarin is found in many plants and is found in high concentrations in certain types of cinnamon, which is one of the most frequent sources for human exposure to the substance. "We started screening natural compounds in neuronal cells and MIC came up as a major hit. Rather than taking MIC immediately into a mouse model we wanted to understand its impact on overall aging and identify its mechanism of action, so we took the work into the worm where we found that MIC is in a different class of molecules that enhance the expression of a key protein, TFEB."
Researchers found that MIC enhanced the activity of transcription factor TFEB, which is a master regulator of genes involved in autophagy and lysosomal functions. Autophagy is the intracellular recycling process whereby cells clean up damaged proteins; it derives its abilities from the lysosome. Researchers found that MIC robustly increased the lifespan of C. elegans while also preventing mitochondrial dysfunction in mammalian cells.
Mechanistically MIC works upstream of TFEB by inhibiting ligand-induced activation of the nuclear hormone receptor DAF-12 (in worms)/FXR (in humans), which in turn induces mitophagy and extends lifespan. FXR is best known for its ability to act in the liver and gut to maintain lipid homeostasis, where it acts to regulate levels of TFEB as part of a feed-fast cycle, but recently TFEB was shown to also be present in brain neurons. FXR is regulated by bile salts which are formed in the gut microbiome. "The gut microbiome impacts the body's use of bile acids. Aging impacts our microbiome. If levels of bile acids aren't correct it hinders mitophagy. That's how FXR can impact neuronal health. Neurons have a lot of mitochondria which makes mitophagy important in terms of neurodegeneration."
Restoring Lost Vascularization Capability via FDPS Inhibition
https://www.fightaging.org/archives/2023/11/restoring-lost-vascularization-capability-via-fdps-inhibition/
The ability of the body to build new blood vessels declines with age. One of the consequences is a loss of capillary density in tissues throughout the body, reducing the supply of nutrients and contributing to harmful changes in the fluid dynamics of the vasculature. Researchers have shown that increasing the ability to build and maintain capillaries via upregulation of VEGF can extend life in mice. Here, researchers report on another approach to increasing the capacity for vascularization in mice. The goal of increasing capillary density is an important one, but few research groups or companies are focused on this in any meaningful way.
The stem cell theory of aging dictates that a decline in the number and/or function of stem cells causes tissue degeneration and aging; however, it still lacks unequivocal experimental support. Here, using lineage tracing and single-cell transcriptomics, we identify a population of CD133+ bone marrow-derived endothelial-like cells (ELCs) as potential endothelial progenitor cells, which contribute to tubular structures in vitro and neovascularization in vivo. We demonstrate that supplementation with wild-type and young ELCs respectively restores neovascularization and extends lifespan in progeric and naturally aged mice.
Mechanistically, we identify an upregulation of farnesyl diphosphate synthase (FDPS) in aged CD133+ ELCs-a key enzyme in isoprenoid biosynthesis. Overexpression of FDPS compromises the neovascularization capacity of CD133+ ELCs, whereas FDPS inhibition by pamidronate enhances neovascularization, improves health measures and extends lifespan in aged mice. These findings highlight stem cell-based strategies for the treatment of progeria and age-related pathologies.
Alzheimer's as an Axonal Damage Condition
https://www.fightaging.org/archives/2023/11/alzheimers-as-an-axonal-damage-condition/
Axons are lengthy projections of the cell body that connect neurons, essential to the function of the brain. Researchers here view what is known of the biochemistry of Alzheimer's disease through the lens of damage to axons. As they point out, the relentless focus on protein aggregation, particularly amyloid-β aggregation, in Alzheimer's disease does tend to crowd out more in-depth discussions of what it is that this protein aggregation actually does to cells.
Alzheimer's disease (AD) is the primary cause of dementia and is anticipated to impose a substantial economic burden in the future. Over a significant period, the widely accepted amyloid cascade hypothesis has guided research efforts, and the recent FDA approval of an anti-amyloid-β antibody, believed to decelerate AD progression, has further solidified its significance. However, the excessive emphasis placed on the amyloid cascade hypothesis has overshadowed the physiological nature of Aβ and tau proteins within axons.
Axons, specialized neuronal structures, sustain damage during the early stages of AD, exerting a pivotal influence on disease progression. In this review, we present a comprehensive summary of the relationship between axonal damage and AD pathology, amalgamating the physiological roles of amyloid-β and tau proteins, along with the impact of AD risk genes such as APOE and TREM2. Furthermore, we underscore the exceptional significance of axonal damage in the context of AD.
Some Cancers Induce Cellular Senescence to Aid in Growth
https://www.fightaging.org/archives/2023/11/some-cancers-induce-cellular-senescence-to-aid-in-growth/
The presence of senescent cells can make a tissue environment more hospitable for cancer, as senescent cells secrete growth factors in addition to pro-inflammatory signals. Researchers have provided evidence for some cancers to aggressively employ the strategy of inducing senescence. Here, a research group notes that this induction of senescence can act to suppress the local immune response to a cancer by co-opting immune cells, making them senescent. It remains an open question as to whether targeting senescent cells for destruction is a good idea in the early stages of a cancer, rather than leaving them in place to attract the immune system to the tumor, but this work suggest that it will be useful, acting to remove pro-cancer signaling.
Cancerous tumors consist of a mixture of cells, the most important of which are cancer stem cells. These cells are capable of establishing new cancerous tumors by evading the immune response. Researchers examined the mechanisms by which cancer stem cells evade immune response in mice models. They showed that cancer stem cells induce senescence in macrophages - the immune cells which are responsible for the first step of the destruction of cancer cells.
The team used two cell lines of glioblastoma tumor, one of which was capable of inducing tumor formation (cancer stem cell) and the other of which was not. In mice models, the cancer stem cells suppressed the proliferation of macrophages; further investigation showed that macrophages cultured with cancer stem cells exhibit senescence or cellular aging. Macrophages were not the only immune cells affected; while the proliferation of T cells was unchanged, their antitumor activity was suppressed due to the immunosuppressive factors produced by senescent macrophages. The team identified interleukin 6 (IL-6) produced by cancer stem cells as the molecule responsible for triggering these effects.
The team also demonstrated that supplementing the mice inoculated with cancer stem cells with a molecule called nicotinamide mononucleotide resulted in the proliferation of non-senescent macrophages and reduced the immunosuppressive factors produced by senescent macrophages, preventing tumor growth and leading to increased survival times in mice. Future work will focus on two avenues: confirming that this discovery holds true for cancers other than glioblastomas, and confirming that the findings apply to cancers in humans.
A Therapy to Reduce Lipoprotein(a) Levels
https://www.fightaging.org/archives/2023/11/a-therapy-to-reduce-lipoproteina-levels/
The research and development community is ever in search of the next statin drug, and a way to reduce lipoprotein(a) levels looks very much like an alternative statin. Statins reduce the amount of cholesterol carried by LDL particles in the bloodstream. Lipoprotein(a) is a carrier of cholesterol, like LDL, and research has shown that high levels correlate with the development of atherosclerotic lesions, as is the case for LDL-cholesterol. That being so, one can't be all that optimistic that a treatment to reduce lipoprotein(a) will actually do much for disease risk. Statins reduce risk of stroke and heart attack resulting from atherosclerosis by, at most, and arguably, 20% or so - levels of cholesterol carried in the bloodstream are not the most important input to the disease process. A quarter of humanity still dies from these conditions in the environment in which everyone who can take statins is taking statins. Statins continue to make a great deal of profit for pharmaceutical companies, however, so developing something that looks very much like a statin? That sounds great to the powers that be.
Findings from a phase 1 trial show that a single dose of an experimental therapy, lepodisiran, produced greater than 94% reductions in blood levels of lipoprotein(a), a key driver of heart disease risk, with the results lasting for nearly a year. Lipoprotein(a), often shortened to just Lp(a), is made in the liver and has similarities to LDL, also known as low-density lipoprotein or "bad cholesterol." Unlike other types of cholesterol particles, Lp(a) levels are 80-90% genetically determined. The structure of the Lp(a) particle causes the accumulation of plaque in arteries which greatly increases the risk of heart attacks and strokes.
Although effective therapies exist to reduce the risk of heart disease by lowering LDL cholesterol and other lipids, currently there are no approved drug treatments to lower Lp(a). Since Lp(a) levels are determined by a person's genes, lifestyle changes (diet or exercise) have no effect. In the trial, participants who received an injection of lepodisiran had lipoprotein(a) levels reduced by the top dose as much as 96% within two weeks and maintained levels more than 94% below baseline for 48 weeks. The drug is a small interfering RNA (siRNA) therapeutic that blocks the messenger RNA needed to manufacture a key component of lipoprotein(a) in the liver.
Semaglutide Use Reduces Heart Attack Incidence in Obese Individuals
https://www.fightaging.org/archives/2023/11/semaglutide-use-reduces-heart-attack-incidence-in-obese-individuals/
Some interesting numbers for the effects of weight loss in obese individuals on risk of age-related disease arise from the use of semaglutide in clinical trials. In the study noted here, treated individuals lost 9% of body weight versus 1% for the placebo arm. The outcome of that is at least as good as the use of statins when it comes to effects on cardiovascular disease. The lesson to take away from this is likely that being overweight is more harmful than most people like to think that it is. Existing data is certainly supportive of that conclusion. Excess visceral fat tissue has been shown to lead to a shorter life expectancy, higher lifetime medical costs, greater incidence of all common age-related disease, and the more of it, the worse the outcome.
In a multicenter, double-blind, randomized, placebo-controlled, event-driven superiority trial, we enrolled patients 45 years of age or older who had preexisting cardiovascular disease and a body-mass index (the weight in kilograms divided by the square of the height in meters) of 27 or greater but no history of diabetes. Patients were randomly assigned in a 1:1 ratio to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in a time-to-first-event analysis. Safety was also assessed.
A total of 17,604 patients were enrolled; 8803 were assigned to receive semaglutide and 8801 to receive placebo. The mean duration of exposure to semaglutide or placebo was 34.2 ± 13.7 months, and the mean duration of follow-up was 39.8 ± 9.4 months. A primary cardiovascular end-point event occurred in 569 of the 8803 patients (6.5%) in the semaglutide group and in 701 of the 8801 patients (8.0%) in the placebo group (hazard ratio, 0.80). Adverse events leading to permanent discontinuation of the trial product occurred in 1461 patients (16.6%) in the semaglutide group and 718 patients (8.2%) in the placebo group.
Assessing Pentadecanoic Acid In Vitro
https://www.fightaging.org/archives/2023/11/assessing-pentadecanoic-acid-in-vitro/
The work on pentadecanoic acid noted here is interesting, but should be taken with a grain of salt given that it is performed in vitro. In general, one should expect any given set of mechanisms in the cell to be associated with many different means of manipulation. It is interesting to see a fatty acid capable of touching on the same mechanisms as rapamycin, but remember that the ability to influence the same mechanistic targets does not necessarily translate to the same ability to produce a modest slowing of aging in animal studies. So the usual advice stands here, to wait for the animal studies before getting too excited.
The BioMAP Diversity PLUS system includes a series of independently run and industry-standard pharmacological assays routinely used to screen and compare molecules for activity profiles and clinical indications as well as safety. Specifically, the BioMAP Diversity PLUS system tests molecules across 12 primary human cell-based systems mimicking various disease states and measures the molecule's effects across 148 clinically relevant biomarkers at four doses. The resulting cell-based phenotypic profile enables valuable insights into potential clinical applications of a compound, as well as identifying shared key activities with other compounds of interest.
Pentadecanoic acid (C15:0), an odd-chain saturated fatty acid, has mounting evidence of being essential to supporting cardiometabolic and liver health. People with low circulating C15:0 concentrations have a higher risk of having or developing type 2 diabetes, heart disease, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis, as well as specific types of cancer. As an essential fatty acid, C15:0 should, by definition, support healthspan, and longevity. Further, C15:0 has mTOR-inhibiting and AMPK-activating activities shared with rapamycin and metformin, respectively. As such, we compared the primary human cell phenotypic profile of C15:0 with acarbose, metformin, and rapamycin using BioMAP Diversity PLUS to objectively evaluate common clinically relevant cell-based activities supportive of an expanded healthspan and lifespan. Based on our findings, we then reviewed the literature for further evidence of C15:0 as a longevity-enhancing nutrient.
At their optimal doses, C15:0 (17 µM) and rapamycin (9 µM) shared 24 activities across 10 cell systems, including anti-inflammatory (e.g., lowered MCP-1, TNFα, IL-10, IL-17A/F), antifibrotic, and anticancer activities, which are further supported by previously published in vitro and in vivo studies. Paired with prior demonstrated abilities for C15:0 to target longevity pathways, hallmarks of aging, aging rate biomarkers, and core components of type 2 diabetes, heart disease, cancer, and nonalcoholic fatty liver disease, our results support C15:0 as an essential nutrient with activities equivalent to, or surpassing, leading longevity-enhancing candidate compounds.
Senescent Cells in the Human Brain
https://www.fightaging.org/archives/2023/11/senescent-cells-in-the-human-brain/
Study of the biochemistry of the human brain is hindered by the difficulty of accessing tissue samples. Most work is conducted on post-mortem tissue rather than samples taken from a living brain (such as during surgery), and few research groups have the necessary connections to obtain these materials. Thus the development of brain organoids is important in this part of the medical research field, even given that most present organoid recipes result in a poor substitute for actual tissue. Here, researchers use post-mortem tissue and organoids to demonstrate that senescent cells are important in the aging of the brain, and in the effects of COVID-19. This is one of many data points to suggest that treatment with senolytics capable of passing the blood-brain barrier (such as the dasatinib and quercetin combination) will be beneficial in older individuals.
Aging is a major risk factor for neurodegenerative diseases, and coronavirus disease 2019 (COVID-19) is linked to severe neurological manifestations. Senescent cells contribute to brain aging, but the impact of virus-induced senescence on neuropathologies is unknown. Here we show that senescent cells accumulate in aged human brain organoids and that senolytics reduce age-related inflammation and rejuvenate transcriptomic aging clocks. In postmortem brains of patients with severe COVID-19 we observed increased senescent cell accumulation compared with age-matched controls. Exposure of human brain organoids to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induced cellular senescence, and transcriptomic analysis revealed a unique SARS-CoV-2 inflammatory signature.
Senolytic treatment of infected brain organoids blocked viral replication and prevented senescence in distinct neuronal populations. In human-ACE2-overexpressing mice, senolytics improved COVID-19 clinical outcomes, promoted dopaminergic neuron survival and alleviated viral and proinflammatory gene expression. Collectively our results demonstrate an important role for cellular senescence in driving brain aging and SARS-CoV-2-induced neuropathology, and a therapeutic benefit of senolytic treatments.
A Diminished State Space View of Cognitive Aging
https://www.fightaging.org/archives/2023/11/a-diminished-state-space-view-of-cognitive-aging/
One can measure aging from the bottom up, looking at the most fundamental changes in cell and tissue biochemistry, or one can measure aging from the top down, looking at decline in specific high-level capabilities of the individual. For the two approaches to meet in the middle remains a distant prospect for even simple tissues, never mind the most complex organs, such as the brain. Therapies to reverse aging will be a going concern long before aging is completely mapped, top to bottom. As an example of starting at the top, in a very conceptual way, one might look at the paper here, and its view of one specific aspect of cognitive aging.
Many new technologies, such as smartphones, computers, or public-access systems (like ticket-vending machines), are a challenge for older adults. One feature that these technologies have in common is that they involve underlying, partially observable, structures (state spaces) that determine the actions that are necessary to reach a certain goal (e.g., to move from one menu to another, to change a function, or to activate a new service).
In this work we provide a theoretical, neurocomputational account to explain these behavioral difficulties in older adults. Based on recent findings from age-comparative computational- and cognitive-neuroscience studies, we propose that age-related impairments in complex goal-directed behavior result from an underlying deficit in the representation of state spaces of cognitive tasks. Furthermore, we suggest that these age-related deficits in adaptive decision-making are due to impoverished neural representations in the orbitofrontal cortex and hippocampus.
Bioprinting Skin with Hair Follicles
https://www.fightaging.org/archives/2023/11/bioprinting-skin-with-hair-follicles/
In that part of the tissue engineering community concerned with trying to reproduce natural skin structure, as best as possible with present technology, bioprinting is currently largely used for research and development rather than directly in clinical application as a regenerative therapy. For example, skin models are used in the screening and testing of topical therapies, and greater fidelity with natural skin gives more relevant information. Skin is a complex structure, in which cells associated with sweat glands and hair follicles appear to be important in coordinating growth and healing. The work noted here is an example of the state of the art in bioprinted skin; it remains to be seen as to the timeline for widespread use in the clinic.
Human skin comprises three major compartments, the hypodermis, the dermis, and the epidermis, each representing a rich cellular and biomolecular diversity. The skin also contains adnexal structures, such as the pilosebaceous unit, which is formed by the hair follicle and sebaceous gland. The pilosebaceous unit is further connected to the sweat apocrine gland, the arrector pili muscle, the underlying vasculature and is in contact with nerve cells. This complex structure is formed by about 15 types of cells distributed in concentric layers of cells of epithelial and mesenchymal origins.
Through life, different skin stem cell populations support the cyclic regeneration of the hair follicle and sebaceous gland. At the base of the hair follicle unit, the dermal papilla region is populated by cells known as dermal papilla cells (DPCs). These cells have a stem cell-like profile that allows the continuous and cyclic regeneration of the hair follicles. This characteristic is also part of the reason why the hair follicle units continue producing fibers in vitro. Furthermore, besides being an important route of chemical penetration into the skin, the pilosebaceous unit plays a crucial role in wound healing by providing cells that migrate into the damaged area and differentiate into the specific epidermal cells, demonstrating the relevance of this structure in skin tissue models for both permeation studies and in regenerative medicine as grafts.
Current approaches fail to adequately introduce complex adnexal structures such as hair follicles within tissue engineered models of skin. Here, we report on the use of 3D bioprinting to incorporate these structures in engineered skin tissues. Spheroids, induced by printing dermal papilla cells (DPCs) and human umbilical vein cells (HUVECs), were precisely printed within a pregelled dermal layer containing fibroblasts. The resulting tissue developed hair follicle-like structures upon maturation, supported by migration of keratinocytes and melanocytes, and their morphology and composition grossly mimicked that of the native skin tissue. Reconstructed skin models with increased complexity that better mimic native adnexal structures can have a substantial impact on regenerative medicine as grafts and efficacy models to test the safety of chemical compounds.
USP30 Inhibition Stops Progression of Parkinson's Disease in Mice
https://www.fightaging.org/archives/2023/11/usp30-inhibition-stops-progression-of-parkinsons-disease-in-mice/
Parkinson's disease arises from the spread of misfolded α-synuclein proteins in the nervous system. This produces a wide array of dysfunction, but the most vulnerable cell population to this particular form of neurodegenerative pathology are domaminergenic cells. Their loss provokes the most evident symptoms of the condition. As noted here, this vulnerability appears to have something to do with clearance of damaged mitochondria, and thus with mitochondrial function more generally. Researchers are investigating ways to improve the situation, such as this representative small molecule approach.
Parkinson's disease is a neurodegenerative disorder caused by the progressive loss of the group of brain cells responsible for producing dopamine, a neurotransmitter that plays a critical role in regulating movement and coordination. As these neurons degenerate and dopamine levels decrease, individuals with Parkinson's disease experience a wide range of symptoms, including tremors, stiffness, and difficulties with balance and coordination.
Evidence suggests the dopamine-producing cells die off in Parkinson's disease because something has gone awry with the clearance of the cells' old and dysfunctional mitochondria - organelles that are the source of cells' energy, sometimes called the powerhouse of the cell. Researchers focused on an enzyme called USP30 which plays a role in this process. In a mouse model engineered to lack the gene that produces the enzyme - known as a "knockout model" because one specific gene has been deleted for the purposes of experimentation - the researchers observed that the loss of USP30 protected against the development of Parkinson's-like motor symptoms, increased clearance of damaged mitochondria in neurons, and protected against the loss of dopamine-producing neurons.
In a second set of experiments, the team validated the knockout studies using a proprietary molecule developed by Mission Therapeutics to block the enzyme's action in the dopamine-producing neurons. As in the knockout mice, inhibiting the enzyme's action increased clearance of dysfunctional mitochondria and protected dopamine-producing neurons.