Fight Aging! Newsletter, March 20th 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/
Longevity Industry Consulting Services
Reason, the founder of Fight Aging! and Repair Biotechnologies, offers strategic consulting services to investors, entrepreneurs, and others interested in the longevity industry and its complexities. To find out more: https://www.fightaging.org/services/
- Reprogramming Tumor Cells into Antigen-Presenting Cells
- The Bisphosphonate Zoledronate as a Senolytic Drug
- Microglia Packed Full of Lipofuscin are Harmful in the Aging Brain
- A Tyrosine Kinase Inhibitor Produces Improvement in Early Stage Alzheimer's Patients
- Insulin Metabolism May Affect Life Span via Effects on Innate Immune Function
- Illustrating that Inflammation is Important in the Progression of Atherosclerosis
- More on Transcriptional Noise in Aging
- Loss of Odor Discrimination is the Earliest Age-Related Loss of Olfaction
- Loss of Ensheathing Glia Contributes to Degeneration in the Aging Fly Brain
- Lowered Dietary Phosphate Slows the Onset of Sarcopenia in Mice
- A Lysosomal Overloading Hypothesis of Alzheimer's Disease
- Reducing Glycerol and Glyceraldehyde Levels Extends Life in Nematodes
- Background on the Funding of Retro Biosciences, an Illustrative Slice of Life for the Longevity Industry and its Backers
- Reprogramming Skin Cells with a Novel Transcription Factor Combination Aids Wound Healing
- T Cells May Play a Role in the Brain Inflammation Characteristic of Neurodegenerative Conditions
Reprogramming Tumor Cells into Antigen-Presenting Cells
Today's research materials describe a clever approach to cancer immunotherapy, focused on the goal of enabling the immune system to better identify cancerous cells. In the past, researchers have made some inroads in training the immune system to attack specific target molecules characteristic of cancerous cells, but this is a slow and expensive process when progressing from single target to single target. Further, any given cancer might be capable of evolving to function without exhibiting any one specific target molecule, and only some cancers of a particular type will exhibit that specific signature molecule to start with.
How might one dramatically improve on the number of targets presented to the immune system? Here, researchers report on reprogramming cancer cells into antigen presenting cells, such as macrophages. Antigen presenting cells, as the name suggests, inform T cells of the adaptive immune system as to targets that they might engage. A macrophage normally ingests potential antigens, fragments them, and then presents the fragments as a part of its distinctive cell surface. These converted cancer cells contain all of the characteristic biochemistry of the cancer, but also act as macrophages, fragmenting and displaying those molecules to educate the adaptive immune system as to the full range of targets it might use to identify and kill the other cells of that cancer.
Scientists transform cancer cells into weapons against cancer
Some of the most promising cancer treatments use the patient's own immune system to attack the cancer, often by taking the brakes off immune responses to cancer or by teaching the immune system to recognize and attack the cancer more vigorously. A better approach would be to train T cells to recognize cancer via processes that more closely mimic the way things naturally occur in the body - like the way a vaccine teaches the immune system to recognize pathogens. T cells learn to recognize pathogens because special antigen presenting cells (APCs) gather pieces of the pathogen and show them to the T cells in a way that tells the T cells, "Here is what the pathogen looks like - go get it."
Something similar in cancer would be for APCs to gather up the many antigens that characterize a cancer cell. That way, instead of T cells being programmed to attack one or a few antigens, they are trained to recognize many cancer antigens and are more likely to wage a multipronged attack on the cancer. Now that researchers have become adept at transforming one kind of cell into another, researchers had a hunch that if they turned cancer cells into a type of APC called macrophages, they would be naturally adept at teaching T cells what to attack.
In the current study, the researchers programmed mouse leukemia cells so that some of them could be induced to transform themselves into APCs. When they tested their cancer vaccine strategy on the mouse immune system, the mice successfully cleared the cancer. Other experiments showed that the cells created from cancer cells were indeed acting as antigen-presenting cells that sensitized T cells to the cancer. "What's more, we showed that the immune system remembered what these cells taught them. When we reintroduced cancer to these mice over 100 days after the initial tumor inoculation, they still had a strong immunological response that protected them."
Reprogramming Cancer into Antigen Presenting Cells as a Novel Immunotherapy
Therapeutic cancer vaccination seeks to elicit activation of tumor-reactive T cells capable of recognizing tumor-associated antigens (TAAs) and eradicating malignant cells. Here, we present a cancer vaccination approach utilizing myeloid lineage reprogramming to directly convert cancer cells into tumor reprogrammed-antigen presenting cells (TR-APCs). Using syngeneic murine leukemia models, we demonstrate that TR-APCs acquire both myeloid phenotype and function, process and present endogenous TAAs, and potently stimulate TAA-specific CD4+ and CD8+ T cells.
In vivo TR-APC induction elicits clonal expansion of cancer-specific T cells, establishes cancer-specific immune memory, and ultimately promotes leukemia eradication. We further show that both hematologic cancers and solid tumors, including sarcomas and carcinomas, are amenable to myeloid-lineage reprogramming into TR-APCs. Finally, we demonstrate the clinical applicability of this approach by generating TR-APCs from primary clinical specimens and stimulating autologous patient-derived T cells. Thus, TR-APCs represent a cancer vaccination therapeutic strategy with broad implications for clinical immuno-oncology.
The Bisphosphonate Zoledronate as a Senolytic Drug
You might recall that in 2011, researchers observed a five year gain in life expectancy versus the general population in a study of 121 older people with osteoporosis who were treated with bisphosphonates. This is a large effect size, at the upper end of what is typically observed in studies of exercise and physical fitness. Other, larger trials have observed reduced mortality with bisphosphonate treatment. A modest degree of effort has gone into attempting to understand the mechanisms that might be involved.
One possible candidate mechanism is the clearance of senescent cells and suppression of the harmful inflammatory signaling produced by lingering senescent cells present in old tissues. Selective destruction of senescent cells via senolytic drugs has been shown to produce impressive degrees of rejuvenation in aged mice. With this in mind, in today's open access paper researchers demonstrate that the bisphosphonate drug zoledronate is in fact either senolytic to a meaningful degree, or acts in other ways to reduce the generation of inflammatory signaling by senescent cells. This is quite interesting.
In vitro and in vivo effects of zoledronate on senescence and senescence-associated secretory phenotype markers
In addition to reducing fracture risk, zoledronate has been found in some studies to decrease mortality in humans and extend lifespan and healthspan in animals. Because senescent cells accumulate with aging and contribute to multiple co-morbidities, the non-skeletal actions of zoledronate could be due to senolytic (killing of senescent cells) or senomorphic (inhibition of the secretion of the senescence-associated secretory phenotype [SASP]) actions.
To test this, we first performed in vitro senescence assays using human lung fibroblasts and DNA repair-deficient mouse embryonic fibroblasts, which demonstrated that zoledronate killed senescent cells with minimal effects on non-senescent cells. Next, in aged mice treated with zoledronate or vehicle for 8 weeks, zoledronate significantly reduced circulating SASP factors, including CCL7, IL-1β, TNFRSF1A, and TGFβ1 and improved grip strength. Analysis of publicly available RNAseq data from CD115+ pre-osteoclastic cells isolated from mice treated with zoledronate demonstrated a significant downregulation of senescence/SASP genes. To establish that these cells are potential senolytic/senomorphic targets of zoledronate, we used single cell proteomic analysis and demonstrated that zoledronate significantly reduced the number of pre-osteoclastic cells and decreased protein levels of p16, p21, and SASP markers in these cells without affecting other immune cell populations.
Collectively, our findings demonstrate that zoledronate has senolytic effects in vitro and modulates senescence/SASP biomarkers in vivo. These data point to the need for additional studies testing zoledronate and/or other bisphosphonate derivatives for senotherapeutic efficacy.
Microglia Packed Full of Lipofuscin are Harmful in the Aging Brain
Molecular waste builds up in the lysosomes of long-lived cells such as neurons, and in cells like microglia that ingest extracellular debris in order to clear it from the brain. Lysosomes are the destination for all cellular waste, where materials are broken down to be recycled. While lysosomes are capable of breaking down near every type of biological molecule that they will encounter, some persistent metabolic byproducts pose a problem. Old tissues are characterized by the presence of what is known as lipofuscin, a toxic mix of the various forms of metabolic waste that the lysosome struggles with. When lysosomes become packed with this waste, cells suffer, as the quality control and clearance processes required for optimal function falter.
In today's research materials, scientists provide evidence for lipofuscin in microglia, the innate immune cells of the brain, to be problematic. This presence of lipofuscin increases with age, and appears to meaningfully contribute to the observed age-related dysfunctions of these cells. Relatedly, activation and inflammatory signaling of microglia is implicated in the onset and progression of neurodegenerative conditions. When researchers clear microglia from the brain, there are improvements - this has been demonstrated numerous times in recent years. Since all microglia are cleared, however, it is hard to claim that benefits result from removal of lipofuscin-bearing microglia versus other subpopulations of these cells.
Fresh understanding of ageing in the brain offers hope for treating neurological diseases
"As the brain ages, fat molecules, cholesterol crystals, metals, and misfolded proteins build up inside autofluorescent microglia, which increase their autofluorescence as a result. Unfortunately, this accumulation of cellular debris also makes it harder for the microglia to perform their essential garbage collection tasks in the brain and to prevent neurological injury and neurodegenerative disease."
"In this study we found - in aged animals - that these microglia adopt a unique, dysfunctional state, which has a number of problematic impacts. For example, there is an increase in cellular stress and damage, an accumulation of fats and iron, alterations to metabolic processes and an increase in production of molecules that overstimulate the immune response. Increasing evidence now suggests that the accumulation of autofluorescent microglia contributes to diseases of ageing and neurodegeneration. If these sub-populations of microglia are highly inflammatory and damaging to the brain, then targeting them could be a new strategy for treating aging-related diseases."
Brain injury accelerates the onset of a reversible age-related microglial phenotype associated with inflammatory neurodegeneration
Lipofuscin is an autofluorescent (AF) pigment formed by lipids and misfolded proteins, which accumulates in postmitotic cells with advanced age. Here, we immunophenotyped microglia in the brain of old C57BL/6 mice (older than 18 months) and demonstrate that in comparison to young mice, one-third of old microglia are AF, characterized by profound changes in lipid and iron content, phagocytic activity, and oxidative stress. Pharmacological depletion of microglia in old mice eliminated the AF microglia following repopulation and reversed microglial dysfunction.
Age-related neurological deficits and neurodegeneration after traumatic brain injury (TBI) were attenuated in old mice lacking AF microglia. Furthermore, increased phagocytic activity, lysosomal burden, and lipid accumulation in microglia persisted for up to 1 year after TBI, were modified by APOE4 genotype, and chronically driven by phagocyte-mediated oxidative stress. Thus, AF may reflect a pathological state in aging microglia associated with increased phagocytosis of neurons and myelin and inflammatory neurodegeneration that can be further accelerated by TBI.
A Tyrosine Kinase Inhibitor Produces Improvement in Early Stage Alzheimer's Patients
Senolytic drugs are those that selectively force senescent cells into programmed cell death. Senescent cells accumulate with age throughout the body, and their pro-inflammatory signaling is disruptive to tissue structure and function when maintained over the long term. Clearance of senescent cells has produced sizable, rapid reversal of age-related disease and improvement in health in mice. There are numerous classes of senolytic small molecule drugs, each class attacking the biochemistry of senescent cells from a different direction in order to force programmed cell death. The well-studied senolytic drug dasatinib is a tyrosine kinase inhibitor, and there is evidence for another tyrosine kinase inhibitor, nintedanib, to also be senolytic.
Today's open access paper concerns ongoing clinical trials of masinitib, another tyrosine kinase inhibitor, as a treatment for Alzheimer's disease. Cellular senescence in brain cells, particularly the supporting cells of the brain such as astrocytes and microglia, is implicated in the progression of Alzheimer's disease. The use of tyrosine kinase inhibitors in this context predates a growing understanding of their relevance to cellular senescence in aging, and so the paper here focuses reducing inflammatory activation of brain cells rather than putting this in terms of cellular senescence. It is unclear as to whether masinitib is in fact senolytic, but it would not be that surprising to find that it is. It is also worth noting that the dasatinib and quercetin senolytic combination is presently in early trials to treat Alzheimer's disease.
Masitinib for mild-to-moderate Alzheimer's disease: results from a randomized, placebo-controlled, phase 3, clinical trial
Masitinib is an oral tyrosine kinase inhibitor that has demonstrated neuroprotective action in neurodegenerative diseases via inhibition of mast cell and microglia/macrophage activity, and which is capable of accumulating within the central nervous system (CNS) at a therapeutically relevant concentration. There is a growing body of evidence implicating mast cells and microglia (types of innate immune cells that are present in the central nervous system), with the pathophysiology of Alzheimer's disease (AD). Masitinib has been shown to restore normal spatial learning performance and promote recovery of synaptic markers in a mouse model of AD, with its synapto-protective action being directly linked to mast cell inhibition. Previously, a small phase 2 trial showed that masitinib slows progression in mild-to-moderate AD patients. Here, we report findings from the first large randomized trial targeting activated neuroimmune cells for treatment of mild-to-moderate AD.
Masitinib was administered as an adjunct therapy to standard of care in 182 patients with mild to moderate dementia due to probable AD. After 24 weeks of treatment, masitinib (4.5 mg/kg/day) significantly slowed cognitive deterioration (as measured by the primary endpoint of ADAS-cog), with acceptable safety. Masitinib (4.5 mg/kg/day) showed significant benefit over placebo according to the primary endpoint of ADAS-cog, -1.46 (representing an overall improvement in cognition) versus 0.69 (representing increased cognitive deterioration), respectively, with a significant between-group difference of -2.15. For the ADCS-ADL primary endpoint, the between-group difference was 1.82, i.e. 1.01 (representing an overall functional improvement) versus -0.81 (representing increased functional deterioration), respectively. Safety was consistent with masitinib's known profile (maculo-papular rash, neutropenia, hypoalbuminemia).
Multiple approved drug treatments and dosages for AD have demonstrated a similar change in ADAS-Cog (approximately 2-point) to that reported for masitinib (4.5 mg/kg/day) and this value is also consistent with published recommendations. The observed improvement in ADAS-Cog for masitinib (4.5 mg/kg/day) relative to control is therefore clinically meaningful. Conversely, results from the masitinib 6.0 mg/kg/day parallel group did not demonstrate any treatment effect. One explanation of this divergent result is that the 6.0 mg/kg/day parallel group placebo arm showed an atypical improvement over 24 weeks, as exemplified by the positive change from baseline in ADCS-ADL score
Insulin Metabolism May Affect Life Span via Effects on Innate Immune Function
Insulin metabolism is one of the better studied areas of biochemistry in connection with aging, and one of the earliest areas of focus for the aging research community. Dysfunction of insulin metabolism, meaning loss of insulin sensitivity, is characteristic of obesity and the slide into type 2 diabetes, and the manifestations of diabetes in some ways resemble accelerated aging. While one should not consider high levels of a single form of dysfunction to be accelerated aging, since normal aging is a specific mix of various forms of damage and dysfunction, it can be worth bearing in mind that there are mechanistic overlaps between diseases and aging.
In today's open access paper, researchers connect insulin sensitivity with better function of the innate immune cells known as macrophages. Better insulin sensitivity ensures that macrophages change their behavior to be more ready to clear molecular waste and damaged cells from tissues, while suppressing inflammatory signaling. The researchers suggest that this could be enough to explain the link between insulin metabolism and life expectancy. Since insulin metabolism touches on near every other aspect of cellular behavior, that is a challenging hypothesis to prove, but it is something to think on. The function and inflammatory state of the immune system is clearly important in aging.
Enhanced insulin-regulated phagocytic activities support extreme health span and longevity in multiple populations
The immune system plays a central role in many processes of age-related non-communicable diseases such as cardiovascular diseases, type 2 diabetes, and dementia. Activated immune functions, which frequently describe as inflammation, has been recognized as part of their pathophysiologies. However, accumulating evidence challenges this assumption and suggests that the immune system may instead get mounting adaptive responses to chronic stressors, prolonging the chances of survival of an organism. To address this argument, one possible way is to investigate the immune signatures in long-lived individuals (LLIs; mean age of greater than 95 years old) and centenarians, the "aging champions" who achieved successful human aging and exhibited medical histories with remarkably low incidences of common age-related disorders. Since inflammaging and immunosenescence is a common feature of chronological aging in ordinary people contributing to enhances risks of mortality at advanced age; this proposes that a better functioning immune system, with stronger pro-survival and stress handling abilities, are likely at play in shaping extreme longevity.
The immune system can be schematically seen as two divisions. The ancestral/innate arm is mainly represented by monocytes, natural killer (NK) and dendritic cells (DC); whereas the adaptive arm is represented by the B lymphocytes and T lymphocytes. As if a functioning immune system requires a homeostatic balance between the two, gene expression profiles of circulating immune cells would likely reveal important clues that are crucial for achieving healthy aging. A recent single-cell transcriptomic study reported that expansion of cytotoxic CD4 T cells is a unique immune signature among supercentenarians; whereas previous bulk transcriptome studies proposed that shift in lymphocyte to myeloid cell ratio, enhanced autophagy-lysosomal function; reduction in ribosomal biosynthesis, or upregulated apoptotic Bcl-xL is however crucial to successful aging. It remains unclear if any common immune features unique to extreme longevity exist among LLIs regardless to their origins; and whether the associated molecular signatures can provide insights for practical translations.
By harnessing the wealth of single-cell and bulk transcriptome datasets available in the public repositories; we uncovered that significant induction of innate immune monocytes with enhanced lysosomal and phagocytic activity is a previously unrecognized, common, and unique immune signature among LLIs from various geographical origins and ethnicities. The life cycle of these monocytes in LLIs is enhanced and primed to a M2-like macrophage phenotype. Monocytes are the major immune cells that express insulin receptor (INSR). Functional characterization revealed an insulin-signaling centric immunometabolism network which supports multiple aspects of phagocytosis. Such reprogramming is associated to a skewed trend of DNA demethylation, particularly at the promoter regions of multiple phagocytic genes, so as a direct transcriptional effect induced by the nuclear INSR. Together, these findings highlighted that preservation of insulin sensitivity hence an active innate monocyte-driven phagocytic activity is a defense mechanism in safeguarding healthy lifespan and extended longevity.
Illustrating that Inflammation is Important in the Progression of Atherosclerosis
Atherosclerosis is a condition of macrophage dysfunction. Macrophages are responsible for clearing the excess and oxidized cholesterol that finds its way into blood vessel walls, but they falter at this task with advancing age. In part this is due to the inflammatory environment, which induces changes in the behavior of macrophages, tipping the balance of activities away from repair and towards further amplication of inflammatory signaling. The research noted here demonstrates the relevance of chronic inflammation to the progression of atherosclerosis in a population of patients on statins, looking at risk of subsequent cardiovascular mortality based on inflammatory status.
Once a patient is on statin therapy, cardiologists typically describe two conditions: "residual cholesterol risk" which can be further reduced with additional lipid-lowering therapy, and "residual inflammatory risk" which can be further reduced with certain drugs that impact vascular inflammation. Whether clinicians should choose to focus on further lowering cholesterol or inflammation has been uncertain and controversial.
Researchers examined data from three recently conducted clinical trials (PROMINENT, REDUCE-IT and STRENGTH) of patients with or at high risk for atherosclerotic disease to understand the relative importance of "residual inflammatory risk" as compared to "residual cholesterol risk" among contemporary statin-treated patients. All patients were receiving aggressive guideline directed medical care including statins, usually at high doses. But cardiovascular event rates in all three trials approached 10 percent at five years. In all three trials, blood levels of high-sensitivity C-reactive protein (hs-CRP, a measure of vascular inflammation) were significantly associated with major adverse cardiovascular events (MACE), cardiovascular mortality, and all-cause mortality.
Moreover, the researchers report that hs-CRP was a more potent predictor of future cardiovascular risk than LDL-cholesterol. For example, among aggressively treated patients already on higher intensity statins, the risks of cardiovascular death and all-cause mortality were more than twice as high among those with the highest levels of CRP when compared to those with the highest levels of cholesterol, differences that were highly statistically significant. Treatments that aggressively lower vascular inflammation need to be incorporated into daily practice if doctors are to maximize patient outcomes.
More on Transcriptional Noise in Aging
As a companion piece to a recent article questioning whether transcriptional noise actually exists as envisaged, this review paper covers what is known and unknown in this part of the field. Transcriptional noise is random variation in the first stage of gene expression, and it is thought to increase with age. It seems likely to be a consequence of the broad variety of changes and dysfunctions that occur in cellular biochemistry in old tissues, an accompaniment to faltering quality control of protein synthesis and altered epigenetics. While easily defined at the high level, transcriptional noise is challenging to measure in a defensible way, and hence there is a good deal of debate over quite fundamental questions relating to this topic.
Increasing stochasticity is a key feature in the aging process. At the molecular level, in addition to genome instability, a well-recognized hallmark of aging, cell-to-cell variation in gene expression was first identified in mouse hearts. With the technological breakthrough in single-cell RNA sequencing, most studies performed in recent years have demonstrated a positive correlation between cell-to-cell variation and age in human pancreatic cells, as well as mouse lymphocytes, lung cells, and muscle stem cells during senescence in vitro. This phenomenon is known as the "transcriptional noise" of aging.
In addition to the increasing evidence in experimental observations, progress also has been made to better define transcriptional noise. Traditionally, transcriptional noise is measured using simple statistical measurements, such as the coefficient of variation, Fano factor, and correlation coefficient. Recently, multiple novel methods have been proposed, e.g., global coordination level analysis, to define transcriptional noise based on network analysis of gene-to-gene coordination. However, remaining challenges include a limited number of wet-lab observations, technical noise in single-cell RNA sequencing, and the lack of a standard and/or optimal data analytical measurement of transcriptional noise. Here, we review the recent technological progress, current knowledge, and challenges to better understand transcriptional noise in aging.
Loss of Odor Discrimination is the Earliest Age-Related Loss of Olfaction
Aspects of the sense of smell are some of the earlier casualties of central nervous system aging. Assessments of age-related olfactory dysfunction can provide some insight into the road to neurodegenerative conditions, as the same underlying mechanisms are at work. Researchers here assessed different aspects of olfaction in aging mice, finding that odor discrimination is first loss. Given the data provided to show that upregulation of NAD+ can slow this loss, we might think that mitochondrial dysfunction is an important contributing mechanism in this form of neurodegeneration.
Olfactory dysfunction is a prevalent symptom and an early marker of age-related neurodegenerative diseases in humans, including Alzheimer's and Parkinson's diseases. However, as olfactory dysfunction is also a common symptom of normal aging, it is important to identify associated behavioral and mechanistic changes that underlie olfactory dysfunction in nonpathological aging. In the present study, we systematically investigated age-related behavioral changes in four specific domains of olfaction and the molecular basis in C57BL/6J mice.
Our results showed that selective loss of odor discrimination was the earliest smelling behavioral change with aging, followed by a decline in odor sensitivity and detection while odor habituation remained in old mice. Compared to behavioral changes related with cognitive and motor functions, smelling loss was among the earliest biomarkers of aging. During aging, metabolites related with oxidative stress, osmolytes, and infection became dysregulated in the olfactory bulb, and G protein coupled receptor-related signaling was significantly down regulated in olfactory bulbs of aged mice. Poly ADP-ribosylation levels, protein expression of DNA damage markers, and inflammation increased significantly in the olfactory bulb of older mice.
Lower NAD+ levels were also detected. Supplementation of NAD+ through nicotinamide riboside in water improved longevity and partially enhanced olfaction in aged mice. Our studies provide mechanistic and biological insights into the olfaction decline during aging and highlight the role of NAD+ for preserving smelling function and general health.
Loss of Ensheathing Glia Contributes to Degeneration in the Aging Fly Brain
The brain-resident innate immune cells known as microglia are thought to play an important part in the age-related decline of cognitive function, and rising dysfunction in brain tissue. In the broader population of microglia in mice and humans, an increase in inflammatory behavior is observed, and likely a major cause of issues in the aging brain. Here, however, researchers focus on a subpopulation of microglia in the fly brain called ensheathing glia that become dysfunctional and decline in number with age. These cells act as a sheath for axons, and thus their loss is understandably problematic. Preventing this loss is shown here to improve brain function and longevity in aging flies. Whether analogous processes are important in the equivalent mammalian microglial cells remains to be determined.
Glia have an emergent role in brain aging and disease. In the Drosophila melanogaster brain, ensheathing glia function as phagocytic cells and respond to acute neuronal damage, analogous to mammalian microglia. We previously reported changes in glia composition over the life of ants and fruit flies, including a decline in the relative proportion of ensheathing glia with time. How these changes influence brain health and life expectancy is unknown.
Here, we show that ensheathing glia but not astrocytes decrease in number during Drosophila melanogaster brain aging. The remaining ensheathing glia display dysregulated expression of genes involved in lipid metabolism and apoptosis, which may lead to lipid droplet accumulation, cellular dysfunction, and death. Inhibition of apoptosis rescued the decline of ensheathing glia with age, improved the neuromotor performance of aged flies, and extended lifespan. Furthermore, an expanded ensheathing glia population prevented amyloid-beta accumulation in a fly model of Alzheimer's disease and delayed the premature death of the diseased animals. These findings suggest that ensheathing glia play a vital role in regulating brain health and animal longevity.
Lowered Dietary Phosphate Slows the Onset of Sarcopenia in Mice
Researchers here find that both reduced phosphate in the diet and use of a phosphate binding drug slow age-related loss of muscle mass in mice. It is an interesting result given the size of the effect. It has been proposed that high levels of phosphates observed in later life are relatively important in the constellation of many contributing mechanisms implicated in the onset of sarcopenia, the name given to this characteristic decline of muscle mass and strength. The data noted here seems a compelling demonstration of the point.
Sarcopenia is defined by the progressive and generalized loss of muscle mass and function associated with aging. We have previously proposed that aging-related hyperphosphataemia is linked with the appearance of sarcopenia signs. Because there are not effective treatments to prevent sarcopenia, except for resistance exercise, we propose here to analyse whether the dietary restriction of phosphate could be a useful strategy to improve muscle function and structure in an animal model of aging.
Five-month-old (young), 24-month-old (old) and 28-month-old (geriatric) male C57BL6 mice were used. Old and geriatric mice were divided into two groups, one fed with a standard diet (0.6% phosphate) and the other fed with a low-phosphate (low-P) diet (0.2% phosphate) for 3 or 7 months, respectively. A phosphate binder, Velphoro, was also supplemented in a group of old mice, mixed with a standard milled diet for 3 months.
Old mice fed with low-P diet showed reduced serum phosphate concentration (16.46 ± 0.77 mg/dL young; 21.24 ± 0.95 mg/dL old; 17.46 ± 0.82 mg/dL low-P diet). Old mice fed with low-P diet displayed 44% more mass in gastrocnemius muscles with respect to old mice. NMRI revealed a significant reduction in T2 relaxation time and increased magnetization transfer and mean diffusivity in low-P diet-treated mice compared with their age-matched controls. The low-phosphate diet increased the fibre size and reduced the fibrotic area by 52% in gastrocnemius muscle with respect to old mice. Twitch force and tetanic force were significantly increased in old mice fed with the low phosphate diet. Physical performance was also improved, increasing gait speed by 30% and reducing transition time in the static rod by 55%. Similar results were found when diet was supplemented with Velphoro.
A Lysosomal Overloading Hypothesis of Alzheimer's Disease
Novel immunotherapies for Alzheimer's disease have in recent years finally succeeded in clearing toxic extracellular amyloid-β aggregates from the brain in human clinical trials. Nonetheless, this advance has failed to meaningfully improve patient outcomes. This outcome has led to renewed theorizing on the mechanisms of Alzheimer's disease, in search of an explanation as to how amyloid-β can be so clearly associated with the condition, but fail as a target for therapy.
Some researchers focus on chronic inflammation as the primary mechanism of disease progression, seeing amyloid-β aggregation as a side-effect at best, while others suggest that amyloid-β is critically important, but inside cells rather than outside cells. Here, researchers discuss a possible role for age-related dysfunctions in the cellular maintenance process of autophagy, specifically focusing on the capability of lysosomes to break down the molecular waste that accumulates within them. Impaired autophagy and accumulation of waste in the lysosome harms cells, and is suggested to produce amyloid-β aggregation outside cells as a side-effect of those harms.
The amyloid precursor protein (APP) is infamous for its putatively critical role in the pathogenesis of Alzheimer's disease (AD). However a recent study found that autolysosome acidification declines in neurons with advancing age more than 4 months before amyloid β-protein (Aβ) is deposited extracellularly. Endolysosome de-acidification increases intraneuronal and secreted levels of Aβ. On the other hand, autolysosome acidification increases the degradation of accumulated Aβ in autophagic vacuoles and promotes glial clearance of oligomeric amyloid-β. Therefore, autolysosome acidification declines directly result in Aβ aggregation.
APP accumulates selectively within enlarged and de-acidified lysosomes. In more compromised yet still intact neurons, profuse Aβ-positive autophagic vacuoles pack into large membrane tubules. Then lysosomal membrane permeabilization, cathepsin release, and lysosomal-mediated cell death occur, accompanied by microglial invasion. Thus, Aβ accumulation may be the "result" rather than the "cause". The finding prompts rethinking of the conventionally accepted sequence of AD plaque formation and may help explain the inefficiency of Aβ/amyloid vaccines and Aβ/amyloid-targeted therapies.
Reducing Glycerol and Glyceraldehyde Levels Extends Life in Nematodes
Researchers here note an approach to extending life by 50% in nematode worms that functions by lowering levels of glycerol and glyceraldehyde in tissues. Lower animals such as nematodes have a far greater plasticity of life span in response to interventions than is the case for mammals. Thus this research is worth taking note of, a suggestion that this area of metabolism is worthy of more attention, but implementing something similar in mammalian species should not be expected to do more than modestly slow aging.
Glycerol and glyceraldehyde are harmful by-products of fat that naturally accumulate over time. Prior aging research in worms, mice, and human cells made researchers in the field suspect that the key to extending lifespan was to activate autophagy, a process that renews broken and old parts in our cells. But researchers were surprised to find that wasn't necessary - the scientists improved worm health and lifespan by 50% with no increase in autophagy at all. They did this by increasing expression a particular gene, adh-1. Doing so prompted the gene to produce more of an enzyme, alcohol dehydrogenase, that prevented the toxicity caused by glycerol and, indirectly, glyceraldehyde. The result was that the worms lived longer, healthier lives.
Findings in lab models such as worms and mice don't always hold true in people, of course. So the researchers took several more steps to see if their lead was as promising as it appeared. First, they confirmed that the enzyme had similar beneficial effects on lifespan in another lab model, yeast. Then they scoured through research looking at gene activity in creatures, including humans, who had undergone fasting or calorie restriction because both fasting and calorie restriction are known to extend healthspan and lifespan. Sure enough, the scientists found increased levels of the anti-aging enzymes in all the mammals tested, including in humans.
The scientists suspect that our levels of glycerol and glyceraldehyde naturally increase over time because they are toxic byproducts of fat, which we store more of as we age. Thus, this approach may offer a way to head off the fat-derived toxicity, extend the number of years we live in good health, and maybe help us shed some extra pounds, too.
Background on the Funding of Retro Biosciences, an Illustrative Slice of Life for the Longevity Industry and its Backers
Retro Biosciences is one of the better funded ventures focused on the treatment of aging to have emerged from the Bay Area centered science, advocacy, and venture communities. The story of how Retro Biosciences came to exist is illustrative of that community, and the way in which a strong interest in human longevity on the part of a few high net worth individuals has shifted in its focus over the past decade. Interested parties have expanded their activities from philanthropic funding of research, initially the only viable approach to make progress, to the addition of much larger investments in startup companies, growing as the biotechnology of treating aging advanced to the point at which it became possible to generate an industry around it.
When a startup called Retro Biosciences led by Joe Betts-LaCroix eased out of stealth mode in mid-2022, it announced it had secured 180 million to bankroll an audacious mission: to add 10 years to the average human life span. It had set up its headquarters in a raw warehouse space near San Francisco just the year before, bolting shipping containers to the concrete floor to quickly make lab space for the scientists who had been enticed to join the company. The entire sum was put up by Sam Altman, the 37-year-old startup guru and investor who is CEO of OpenAI. He says he's emptied his bank account to fund two other very different but equally ambitious goals: limitless energy and extended life span.
Altman's investment in Retro is among the largest ever by an individual into a startup pursuing human longevity. Altman has long been a prominent figure in the Silicon Valley scene, where he previously ran the startup incubator Y Combinator in San Francisco. Altman says he has been placing bets in areas where underlying trends make him think technologies that look impossible today might actually work relatively soon.
About eight years ago, Altman became interested in so-called "young blood" research. These were studies in which scientists sewed young and old mice together so that they shared one blood system. The surprise: the old mice seemed to be partly rejuvenated. In 2018, Y Combinator launched a special course for biotech companies, inviting those with "radical anti-aging schemes" to apply, but before long, Altman moved away from Y Combinator to focus on his growing role at OpenAI.
Then, in 2020, researchers in California showed they could achieve an effect similar to young blood by replacing the plasma of old mice with salt water and albumin. "Sam called me up and said 'Holy moly, did you see this plasma intervention paper?'" recalls Betts-LaCroix, who had once been the part-time biotech partner at Y Combinator and still leads a meetup for longevity enthusiasts. Betts-LaCroix agreed that it was cool and some company should pursue it. "How about I fund you to do it?" Altman said. But Betts-LaCroix was already working on a different longevity-related idea, cellular reprogramming. Altman's response: "Why don't you do all those things?" Betts-LaCroix recalls saying. "I'll do it. I'll build a multi-program company around aging biology, and that is the big play. He was like, 'Great - let's go for it.'"
Reprogramming Skin Cells with a Novel Transcription Factor Combination Aids Wound Healing
Researchers here show that reprogramming of mesenchymal cells present in wounded skin produces a population of epithelial progenitor cells that induce the creation of new hair follicles and sweat glands during the healing process. Mammalian skin does not normally regenerate these features, an issue that many research groups have sought to address. This is an interesting advance, to be added to some of the other approaches that are claimed to more completely regenerate injured skin.
Mammalian skin appendages, such as hair follicles and sweat glands, are complex mini-organs formed during skin development. As wounds heal, the resulting scar tissue lacks skin appendages. The clinical regeneration of skin appendages is an ongoing challenge. Skin epithelial tissues have been regenerated in vivo by cellular reprogramming, but the de novo generation of skin appendages has not previously been achieved.
Here, we show that transplantation of a type of epithelial cell and two types of mesenchymal cells, reprogrammed from adult mouse subcutaneous mesenchymal cells to mimic developing skin cells, resulted in the generation of skin-appendage-like structures. After recent advances in cellular reprogramming we have developed a method to generate skin epithelial tissues by in vivo reprogramming of wound-resident mesenchymal cells with four transcription factors (DNP63A, GRHL2, TFAP2A, and cMYC), resulting in cells with the ability to form stratified epithelia.
With the development of a new AAV serotype, in vivo reprogramming of wound-resident cells with the same reprogramming factors generates skin with de novo appendages in adult mice. These findings may provide new therapeutic avenues for skin regeneration and frequent aging-associated skin appendage disorders, such as hair loss and dry skin, and may extend to other tissues and organs. This study also provides the potential for de novo generation of complex organs in vivo.
T Cells May Play a Role in the Brain Inflammation Characteristic of Neurodegenerative Conditions
Alzheimer's disease, and other forms of neurodegenerative condition, are characterized by chronic inflammation in brain tissue. Unresolved inflammatory signaling is disruptive of tissue structure and function. Here, researchers provide evidence for T cells to become involved in this process. Normally T cells of the adaptive immune system do not enter the brain in any great numbers, but those numbers are greater in Alzheimer's patients. Researchers here show that eliminating these T cells slows the progression of neurodegeneration in animal models, suggesting that this approach may be worth trying in human clinical trials.
Many of the immunity-focused Alzheimer's drugs under development are aimed at microglia, the brain's resident immune cells, which can injure brain tissue if they're activated at the wrong time or in the wrong way. A new study indicates that microglia partner with another type of immune cell - T cells - to cause neurodegeneration. Studying mice with Alzheimer's-like damage in their brains due to the protein tau, the researchers discovered that microglia attract powerful cell-killing T cells into the brain, and that most of the neurodegeneration could be avoided by blocking the T cells' entry or activation. The findings suggest that targeting T cells is an alternative route to preventing neurodegeneration and treating Alzheimer's disease and related diseases involving tau, collectively known as tauopathies.
"This could really change the way we think about developing treatments for Alzheimer's disease and related conditions. Before this study, we knew that T cells were increased in the brains of people with Alzheimer's disease and other tauopathies, but we didn't know for sure that they caused neurodegeneration. These findings open up exciting new therapeutic approaches. Some widely used drugs target T cells. Fingolomid, for example, is commonly used to treat multiple sclerosis, which is an autoimmune disease of the brain and spinal cord. It's likely that some drugs that act on T cells could be moved into clinical trials for Alzheimer's disease and other tauopathies if these drugs are protective in animal models."