Fight Aging!

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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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/

Contents

• Cognitive Impairment Correlates with an Altered Gut Microbiome
• Progress Towards Rejuvenation as a Matter of Investment versus a Matter of Time
• A Study of Metabolite Profiles in Healthy Individuals Across Age Groups
• Cellular Senescence in the Aging of Bone Tissue
• Defining the Longevity Industry to Exclude Those Who Circumvent Rigorous Clinical Trials
• The Gut-Brain Axis in Age-Related Neurodegeneration
• The Aging of the Enteric Nervous System
• Age-Associated B Cells Correlate with Impaired Immune Response
• A Novel Scaffold Material Accelerates Bone Regeneration in Rats
• Breaking Down Methionine as an Alternative to a Low Methionine Diet
• A Seed and Soil Model for Gut Microbiome Aging to Contribute to Alzheimer's Disease
• Planarians Use a Similar Strategy to Embryonic Reprogramming to Maintain Immortality
• Mitochondrial Dysfunction as a Contribution to Muscle Aging
• ATG4B Overexpression Increases Life Span in Flies
• Lipid Droplet Accumulation in Aging and Age-Related Disease

Cognitive Impairment Correlates with an Altered Gut Microbiome
https://www.fightaging.org/archives/2023/07/cognitive-impairment-correlates-with-an-altered-gut-microbiome/

Today's open access papers report on studies of the gut microbiome in older individuals exhibiting cognitive impairment. They add to a growing body of evidence for specific changes in the gut microbiome to contribute to age-related neurodegenerative conditions. The most obvious way in which this might happen is via a greater number of microbes capable of provoking a state of constant inflammation, either directly by engaging with the immune system, or more indirectly by contributing to dysfunction of the intestinal barrier, and thus allowing leakage of unwanted microbes and microbial metabolites into tissue. But it is also possible that loss of beneficial metabolites is a meaningful issue in later life.

The relative sizes of microbial populations making up the gut microbiome change with age, for reasons still under exploration, but in which the aging of the immune system may play a sizable role. The gut microbiome becomes more uniquely dysfunctional from individual to individual, but it is nonetheless the case that studies of cognitive decline and dementia are finding features of the gut microbiome that can be used to distinguish between healthy and cognitively impaired individuals.

It is not all that challenging to reset an aged gut microbiome via fecal microbiota transplantation from a young individual, at least not on an individual basis, without considering all of the overhead of regulatory approval. Fecal microbiota transplantation improves health and extends life in animal studies. There comes a point at which investigation must give way to clinical trials as a means to test whether restoration of a more youthful gut microbiome can meaningfully postpone neurodegenerative conditions; it seems a reasonable wager, given what is known.

Altered gut microbiota in older adults with mild cognitive impairment: a case-control study

Gut microbiota alterations in mild cognitive impairment (MCI) are inconsistent and remain to be understood. This study aims to investigate the gut microbial composition associated with MCI, cognitive functions, and structural brain differences. A nested case-control study was conducted in a community-based prospective cohort where detailed cognitive functions and structural brain images were collected. Thirty-one individuals with MCI were matched to sixty-five cognitively normal controls by age strata, gender, and urban/rural area. Fecal samples were examined using 16S ribosomal RNA (rRNA) sequencing. Compositional differences between the two groups were identified and correlated with the cognitive functions and volumes/thickness of brain structures.

There was no significant difference in alpha diversity and beta diversity between MCIs and cognitively normal older adults. However, the abundance of the genus Ruminococcus, Butyricimonas, and Oxalobacter decreased in MCI patients, while an increased abundance of nine other genera, such as Flavonifractor, were found in MCIs. Altered genera discriminated MCI patients well from controls and were associated with attention and executive function.

Gut microbiota and intestinal barrier function in subjects with cognitive impairments: a cross-sectional study

To investigate the differences in gut microbial composition, intestinal barrier function, and systemic inflammation in patients with Alzheimer's disease (AD) or mild cognitive impairment (MCI), and normal control (NC) cases, a total of 118 subjects (45 AD, 38 MCI, and 35 NC) were recruited. Cognitive function was assessed using Mini-Mental State Examination (MMSE), and Montreal Cognitive Assessment Scale (MoCA). Functional ability was assessed using Activity of Daily Living Scale (ADL). The composition of gut microbiome was examined by 16S rRNA high-throughput sequencing. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) was used to predict functional transfer of gut microbiota. Gut barrier dysfunction was evaluated by measuring the levels of diamine oxidase (DAO), D-lactic acid (DA), and endotoxin. The serum high-sensitivity C-reactive protein (hs-CRP) level was used to indicate systemic inflammation.

Compared with normal controls, patients with cognitive impairments (AD and MCI) had lower abundance of Dorea and higher levels of DAO, DA, and endotoxin. Kyoto Encyclopedia of Genes and Genomes (KEGG) results showed that the pathways related to glycan biosynthesis and metabolism increased in MCI patients, while the ones related to membrane transport decreased. The abundance of Bacteroides and Faecalibacterium was negatively correlated with the content of endotoxin, and positively correlated with the scores of MMSE and MoCA. The hs-CRP levels were similar among the three groups. A significant negative correlation was observed between the severity of gut barrier dysfunction and cognitive function.

Progress Towards Rejuvenation as a Matter of Investment versus a Matter of Time
https://www.fightaging.org/archives/2023/07/progress-towards-rejuvenation-as-a-matter-of-investment-versus-a-matter-of-time/

It is not hard to argue that there is too little investment in progress towards the treatment of aging as a medical condition. Collectively, the underlying mechanisms of degenerative aging are the cause of two-thirds of human mortality, and likely a somewhat greater fraction of loss of function, suffering, and pain. The cost of that mortality is vast, no matter how one likes to model the value of a human life, or a year spent alive in good health. This is much the same argument that can be made for greater investment in medical research in general. Medical research funding as a whole is a very, very tiny fraction of the costs that coping with currently incurable, unmanageable conditions impose upon us. But our species isn't really all that rational when it comes to collective action, whether or not the topic is saving our lives.

It seems inevitable that the urge for scientific progress will at some point lead to the development of impressive rejuvenation therapies. Rejuvenation is just a special case of medicine, which is just a special case of control over complex molecular systems. The ideal of achieving meaningful progress towards that broader goal is entrenched into the scientific and technological culture of the past century; it seems likely to continue. Today's cutting edge technology demonstrations in exerting fine control over aspects of our cellular biochemistry will be commonplace building blocks in the toolkit in three decades, and ancient history in six decades. But inevitability over the longer term certainly doesn't translate to inevitability on useful timescales, such as sometime before you or I become too old or too dead to benefit from novel approaches to controlling the processes that drive aging.

In the short term, there are always challenges inherent in selling investors on a plan of action, in the obstacles and costs imposed by regulators, in the perverse incentives operating in the pharma industry, in persuading people to support the cause, in the right entrepreneurs having the right ideas and connecting with the right scientists. One can throw as much funding as one likes at a problem, but many component parts of the intricate dance involving many different humans trying to make progress on a given problem simply can't be compressed to much below a few years. In the present regulatory system, and culture of science, it is always going to take more than a decade to move from lab to widespread availability for most ultimately successful programs, even given many well-funded, competing factions working on their versions of a solution.

Curing aging is a question of investment, not time

"When you think about treating aging, what we're really talking about is treating this whole range of different diseases - cancer, heart disease, stroke, dementia - all of these things are caused by the aging process. So, there's a huge opportunity to make a big difference in the world. If these drugs can potentially slow down or reverse the aging process, then they ultimately have a market of every living human,. You can imagine a situation where everyone over the age of 50 or 60, once they've accumulated enough of whatever age-related change your drug is targeting, will want to start using that medication. It's going to be a completely new paradigm for medical treatment, and it's a huge opportunity for investors."

Of course, investing in longevity isn't as simple as it sounds - the field is vast and diverse, with hundreds of companies targeting different hallmarks, mechanisms, and drivers of aging. Andrew Steele's hope is that investment will also extend into the basic science needed to advance some of these areas to the point where potential treatments are ready to turn into biotech or pharma endeavors. "I believe these treatments will often turn out to be complementary to other areas of longevity development. I often talk about a cure for aging, but that doesn't mean I think it's going to be a single pill - we're probably going to have dozens of different approaches to tackle lots of different age-related changes. So, I'd really encourage investors to go out and try and find some of these other age-related changes that aren't getting aren't getting quite so much limelight."

Longevity science is a field where predictions about timeframes to achieving certain milestones are often bandied around. It's a practice that Andrew Steele feels is unhelpful. "I think the way people often try and give their predictions as a certain number of years away is a bit wrongheaded. I think we should really think about developments in science as being a certain investment away from fruition." Essentially there are a certain number of "nerd hours" between where we are now and getting to the point of being able to treat the aging process sufficiently well to bring it under medical control. And those nerd hours cost money. "I don't know how much money that's necessarily going to involve - it's hard to look at current levels of investment and multiply that up. But what I do know is, the more we invest, the faster a lot of this science can progress."

A Study of Metabolite Profiles in Healthy Individuals Across Age Groups
https://www.fightaging.org/archives/2023/07/a-study-of-metabolite-profiles-in-healthy-individuals-across-age-groups/

In today's open access paper, researchers report on a study of age-related changes in metabolite profiles in blood, muscle, and urine, with samples taken from healthy members of age groups spanning the 20s to 80s. As might be expected, the results point to many of the usual suspects in aging, such as senescent cell burden and mitochondrial dysfunction.

It is certainly possible to use metabolomic data to construct aging clocks in much the same way as for epigenetic data, and some researchers have done just that in recent years. There are indeed characteristic changes in a range of metabolite levels that appear to reflect biological age, the burden of damage and dysfunction, rather than chronological age.

Cross-sectional analysis of healthy individuals across decades: Aging signatures across multiple physiological compartments

Human studies make use of biomarker changes in fluids and tissues, such as blood, skeletal muscle, and urine, that occur during the aging process to infer biological changes due to aging per se. These studies are made even more complex by the difficulty in distinguishing between changes compensatory to the emergence of pathology and those that simply reflect aging itself. In addition, findings from studies that investigated age-related changes in the metabolome that occurred in just one compartment, such as plasma or serum, may not necessarily translate to other biological fluids or tissues.

We hypothesized that simultaneously investigating age-related differences in various fluid and tissue compartments may shed more light on the underlying mechanisms that drive changes in the metabolome with age and that ultimately contribute to the phenotypic manifestations of aging. Here, we report the results of a comprehensive profiling of age-related metabolomic changes across three compartments simultaneously: the circulatory system (plasma), the excretory system (urine), and a solid organ (skeletal muscle). To minimize the interference of changes in metabolites reactive to pathology, we enrolled in this study individuals that were healthy based on a comprehensive clinical evaluation performed by trained health professionals. To reduce variability that can result from different quantification methods, the same targeted metabolomic platform was used for all compartments. Herein, we carry out a cross-sectional analysis of 'healthy' individuals who were free from disease to formulate hypotheses based on the metabolic exchanges that occur between different compartments with aging.

Here, we summarize the metabolic pathways that emerged from our analysis of metabolites in plasma, muscle, and urine. These pathways include inflammation and cellular senescence, microbial metabolism, mitochondrial health, sphingolipid metabolism, lysosomal membrane permeabilization, vascular aging, and kidney function. It is important to underline that while these biological mechanisms are far from being a comprehensive list of the biological processes at play over human life spans, they provide insight into some of the basic metabolomic age signatures of cross compartmental, interconnected changes.

Cellular Senescence in the Aging of Bone Tissue
https://www.fightaging.org/archives/2023/07/cellular-senescence-in-the-aging-of-bone-tissue/

Cells become senescent constantly, throughout life and throughout the body. Most such cells have reached the Hayflick limit on replication, but cells can also become senescent in response to damage, stress, or the signaling of other senescent cells. In youth, senescent cells are efficiently cleared by the immune system, but this clearance falters with age for reasons that are incompletely understood at the present time. The consequence of a mismatch between pace of creation and pace of clearance is a growing burden of lingering senescent cells. These cells secrete a mix of signals, the senescence-associated secretory phenotype (SASP), that is disruptive to tissue structure and function, and provokes continual, unresolved inflammation. This directly contributes to the onset and progression of many age-related conditions.

In today's open access paper, researchers discuss the presence of senescent cells and SASP in the context of bone tissue specifically. Bone loses density with age, leading to osteoporosis. This results from an imbalance between the activities of osteoblasts, creating bone, and osteoclasts, removing bone. Many contributing factors lead to a growing gap that favors the breakdown of bone tissue by osteoclasts, and the signaling produced by senescent cells is one such factor. Further, bone is a tissue of significant size, and the SASP produced by senescent cells spreads throughout the body. The larger the organ, the greater the impact as some proportion of cells becomes senescent. Cellular senescence in larger tissues such as skin, muscle, and bone may well have meaningful harmful effects elsewhere in the body.

"Bone-SASP" in Skeletal Aging

Substantial evidence supports the causal role of cellular senescence in bone tissue during natural aging, premature aging syndromes, and many age-associated skeletal disorders, such as osteoporosis and osteoathritis. A central mechanism by which senescent cells expand the senescence program and impair the bone and bone marrow microenvironment is via senescent bone cell-associated SASP, namely "bone-SASP." It is now well recognized that the SASP is highly heterogeneous, varies depending on cell type and the senescence-inducing stimulus, and is very dynamic, changing over time after the stimulus. Thus, it is important to use a proteomic, unbiased approach to gain insights into highly complex SASP profiles.

However, in most studies of the detection of bone-SASP in pathological conditions such as the progeria-associated bone disorders, osteoarthritis, and osteoporosis, unbiased profiling of the SASP factors was not conducted. Only chosen panels of inflammatory factors and cytokines were detected. Given that the newly generated SenMayo dataset identifies bone-SASP across tissues and species with high fidelity, further detailed characterization and comprehensive identification of the bone-SASP in different age-associated skeletal conditions are warranted.

Recent studies suggest that the SASP, as a feature of cellular senescence, not only exerts a detrimental effect locally but may also cause systemic adverse effects. Although the SASP has an endocrine effect on regulating the activities of tissues and organs at remote sites, the endocrine role of the bone-SASP remains largely unexplored. Recent evidence revealed that PDGF-BB produced by senescent preosteoclasts serve as a systemic pro-aging factor that contributes to age-associated increase in arterial stiffness and cerebrovascular impairment. Further assessment is needed of the involvement of bone-derived PDGF-BB in the aging process of other organ systems to validate its endocrine function.

In summary, research into the endocrine role of senescent cells is still in the early stage. Given that some bone-SASP factors identified to date are important inflammatory factors and pro-aging factors, there is no doubt that the systemic effect of bone-SASP factors will become one of the main topics in the field of skeletal research.

Defining the Longevity Industry to Exclude Those Who Circumvent Rigorous Clinical Trials
https://www.fightaging.org/archives/2023/07/defining-the-longevity-industry-to-exclude-those-who-circumvent-rigorous-clinical-trials/

As the longevity industry grows, the need for investment grows with it. A big leap in funding is needed to move from preclinical to clinical development, and ever more companies are arriving at the point of making that transition. Raising the few million in seed funding needed for a small lab team to produce proof of principle studies to demonstrate that a novel therapy works in mice is a very different prospect in comparison to raising tens of millions to conduct GMP manufacturing and phase II clinical trials in humans, never mind the even larger sums needed for later phase III trials. The types of investors to participate at early and later stages are very different, with very different ideas of risk. It is typically the case that larger the check, the more institutional and conservative the investor.

Institutional, conservative biotech investors care greatly about the way in which they are perceived, since their ability to raise funds from limited partners is very much affected by that perception. When it comes to investing in the longevity industry, conservative investors are attracted by the potential for profit, but bothered by the long-standing existence of a fraudulent "anti-aging" marketplace, alongside numerous groups claiming membership of the longevity industry while selling supplements or treatments via medical tourism with claims that are in no way backed by rigorous evidence. These investors have carefully cultivated reputations, and fear the loss of reputation that results from investing sizable funding into ventures that fail. And some fraction of ventures always fail. When those ventures were by-the-book, nothing-new-here, conservative endeavors that checked all of the proper boxes, that can be forgiven. But venturing out into the unknown? That is less forgivable.

Thus as the longevity industry matures, elements within it are creating industry associations and paving the way to a perception of the longevity industry as a by-the-book, rigorous, nothing-new-here endeavor, just like the rest of the medical biotechnology space. They draw a circle that excludes everyone who sidesteps the existing regulatory system for drug development: the supplement companies; the cosmetic companies; the companies focusing on medical tourism rather than the FDA; and so forth. Today's position statement is authored by the founders, investors, and leadership of a number of the longevity industry companies closest to clinical trials. This is a part of the process of laying the groundwork to make it easier to find the much greater funding needed for the phase II and phase III trials that lie ahead.

Defining a longevity biotechnology company

The Longevity Biotechnology Association (LBA) is a non-profit organization created to foster collaboration, propose guidelines for industry, educate stakeholders, and translate geroscience to prevent the diseases associated with aging and extend healthspan. Billions in funding are being allocated to basic and translational research in aging biology, but parameters and guide rails for the longevity biotechnology industry remain undefined. The efficacy of a new intervention can only be rigorously demonstrated by a sufficiently powered clinical trial. Today, there are products on the market that claim to boost longevity but lack robust scientific evidence in humans to support these claims. Academic scientists, drug developers, and entrepreneurs developing new drugs arising from aging research need to direct their efforts toward elucidating the mechanisms of action of potential interventions and conducting human trials. Similarly, investors, regulators, members of the media and others require a framework to evaluate the claims made by translational longevity biotechnology projects and their potential to demonstrate effectiveness of an intervention in humans.

The LBA proposed framework for a longevity biotechnology company includes four pillars: (1) mission, (2) drug discovery approach, (3) initial clinical development and regulatory approval, and (4) targeting multi-morbidity and healthspan. By creating a framework that defines best practices in longevity biotechnology, we hope to facilitate communication with audiences that include drug developers, investors, regulators, policymakers, journalists and the general public. Clarification of the field's goals and approaches will help to direct resources to efforts with the greatest potential for trial success and regulatory approval, move innovations from the bench into clinical practice, and ultimately improve the lives of older adults.

Interest and investment into the longevity drug development space continue to grow, with the number of players in the sector expected to increase. Following the proposed framework by having a specific mission, generating a drug that targets known hallmark mechanisms, and going through the processes of early- and late-stage clinical trials will demonstrate to any scientist, investor, company, journalist or member of the public that a specific organization is positioned to contribute positively to the field of longevity biotechnology.

When a novel field of research captures the interest of academics, investors and the public, it is common for various approaches to proliferate. Some of these approaches will leverage novel science to yield patient benefit. However, as noted, less rigorous actors might exploit the public interest to sell products to consumers and patients. The onus rests with the experts within the new research field to help non-experts distinguish between the two. In the early 2000's this was done expertly for the stem cell field by the International Society for Stem Cell Research (ISSCR), which has helped maintain and update those standards in recent decades. We helped create the LBA as a non-profit entity to achieve a similar goal. Although the organization is still young, we have put forward this framework to identify those efforts that have a high likelihood of contributing to the goal of not just creating new interventions based on aging research, but also demonstrating that the interventions increase human healthspan in clinical trials.

The Gut-Brain Axis in Age-Related Neurodegeneration
https://www.fightaging.org/archives/2023/07/the-gut-brain-axis-in-age-related-neurodegeneration/

The various microbial populations making up the gut microbiome shift in relative size with age, favoring harmful microbes capable of provoking chronic inflammation over helpful microbes that manufacture beneficial metabolites. That this aging of the gut microbiome can contribute to the chronic inflammation of old age implicates it in the development of many age-related conditions. Unresolved inflammatory signaling is known to be disruptive to cell and tissue function throughout the body, and neurodegenerative conditions in particular exhibit a strong inflammatory component to pathology. Restoring a more youthful gut microbiome may prove to be a useful class of therapy.

A progressive degradation of the brain's structure and function, which results in a reduction in cognitive and motor skills, characterizes neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). The gut-brain axis (GBA) is now known to have a crucial role in the emergence of NDs. The gut microbiota is a conduit for the GBA, a two-way communication system between the gut and the brain. The myriad microorganisms that make up the gut microbiota can affect brain physiology by transmitting numerous microbial chemicals from the gut to the brain via the GBA or neurological system.

The synthesis of neurotransmitters, the immunological response, and the metabolism of lipids and glucose have all been demonstrated to be impacted by alterations in the gut microbiota, such as an imbalance of helpful and harmful bacteria. In order to develop innovative interventions and clinical therapies for NDs, it is crucial to comprehend the participation of the gut microbiota in these conditions. In addition to using antibiotics and other drugs to target particular bacterial species that may be a factor in NDs, this also includes using probiotics and other fecal microbiota transplantation to maintain a healthy gut microbiota.

In conclusion, the examination of the GBA can aid in understanding the etiology and development of NDs, which may benefit the improvement of clinical treatments for these disorders and ND interventions. This review indicates existing knowledge about the involvement of microbiota present in the gut in NDs and potential treatment options.

The Aging of the Enteric Nervous System
https://www.fightaging.org/archives/2023/07/the-aging-of-the-enteric-nervous-system/

The enteric nervous system is the nervous system of the intestines, and likely an important part of the relationship between the gut microbiome and the brain. One of the more interesting parts of this review paper is the discussion regarding relationships between the gut microbiome and enteric nervous system. All too little is known in detail, even while it is possible to find reports of specific associations and points of communication between gut microbiome and nervous system. Given the attention to measuring and altering the balance of populations in the gut microbiome, one might hope that the advent of ways to sizeably and favorably adjust the gut microbiome will meaningfully improve late life health.

The gut and the brain communicate via the nervous system, hormones, microbiota-mediated substances, and the immune system. These intricate interactions have led to the term "gut-brain axis". Unlike the brain-which is somewhat protected-the gut is exposed to a variety of factors throughout life and, consequently, might be either more vulnerable or better adapted to respond to these challenges. Alterations in gut function are common in the elder population and associated with many human pathologies, including neurodegenerative diseases. Different studies suggest that changes in the nervous system of the gut, the enteric nervous system (ENS), during aging may result in gastrointestinal dysfunction and initiate human pathologies of the brain via its interconnection with the gut.

This review aims at summarizing the contribution of normal cellular aging to the age-associated physiological changes of the ENS. Morphological alterations and degeneration of the aging ENS are observed in different animal models and humans, albeit with considerable variability. The aging phenotypes and pathophysiological mechanisms of the aging ENS have highlighted the involvement of enteric neurons in age-related diseases of the central nervous system such as Alzheimer's or Parkinson's disease. To further elucidate such mechanisms, the ENS constitutes a promising source of material for diagnosis and therapeutic predictions, as it is more accessible than the brain.

Age-Associated B Cells Correlate with Impaired Immune Response
https://www.fightaging.org/archives/2023/07/age-associated-b-cells-correlate-with-impaired-immune-response/

Age-associated B cells are one of a number of dysfunctional or maladaptive immune cell subpopulations that appear in increasing numbers in later late, and which likely impair the many functions of the immune system by their presence. Clearing all B cells rather than trying to selectively clear age-associated B cells is a viable proposition, as the B cell population regenerates quite rapidly following clearance, and the new cells lack the age-associated B cell phenotype. This has been demonstrated in animal models, but has yet to make it to the clinic as a treatment to improve the aged immune system.

Age-associated B cells (ABC) accumulate with age and in individuals with different immunological disorders, including cancer patients treated with immune checkpoint blockade and those with inborn errors of immunity. Here, we investigate whether ABCs from different conditions are similar and how they impact the longitudinal level of the COVID-19 vaccine response.

Single-cell RNA sequencing indicates that ABCs with distinct aetiologies have common transcriptional profiles and can be categorised according to their expression of immune genes, such as the autoimmune regulator (AIRE). Furthermore, higher baseline ABC frequency correlates with decreased levels of antigen-specific memory B cells and reduced neutralising capacity against SARS-CoV-2.

ABCs express high levels of the inhibitory FcγRIIB receptor and are distinctive in their ability to bind immune complexes, which could contribute to diminish vaccine responses either directly, or indirectly via enhanced clearance of immune complexed-antigen. Expansion of ABCs may, therefore, serve as a biomarker identifying individuals at risk of suboptimal responses to vaccination.

A Novel Scaffold Material Accelerates Bone Regeneration in Rats
https://www.fightaging.org/archives/2023/07/a-novel-scaffold-material-accelerates-bone-regeneration-in-rats/

Researchers here demonstrate accelerated healing of bone loss in rats, using a novel implanted scaffolding material that provides a nanostructure to encourage cell growth and repair activities. As described in this paper, bone is made up of both harder and softer small-scale structures, and suitable choices of material and structure that better mimic these features can provoke osteogenic cells into greater activity than would otherwise be the case.

Several studies have shown that nanosilicate-reinforced scaffolds are suitable for bone regeneration. However, hydrogels are inherently too soft for load-bearing bone defects of critical sizes, and hard scaffolds typically do not provide a suitable three-dimensional (3D) microenvironment for cells to thrive, grow, and differentiate naturally. In this study, we bypass these long-standing challenges by fabricating a cell-free multi-level implant consisting of a porous and hard bone-like framework capable of providing load-bearing support and a softer native-like phase that has been reinforced with nanosilicates.

The system was tested with rat bone marrow mesenchymal stem cells in vitro and as a cell-free system in a critical-sized rat bone defect. Overall, our combinatorial and multi-level implant design displayed remarkable osteoconductivity in vitro without differentiation factors, expressing significant levels of osteogenic markers compared to unmodified groups. Moreover, after 8 weeks of implantation, histological and immunohistochemical assays indicated that the cell-free scaffolds enhanced bone repair up to approximately 84% following a near-complete defect healing. Overall, our results suggest that the proposed nanosilicate bioceramic implant could herald a new age in the field of orthopedics.

Breaking Down Methionine as an Alternative to a Low Methionine Diet
https://www.fightaging.org/archives/2023/07/breaking-down-methionine-as-an-alternative-to-a-low-methionine-diet/

In animal studies, reduced intake of the essential amino acid methionine mimics many of the beneficial effects of calorie restriction on long-term health and life span, even when calorie intake is maintained at the same level as the control groups. One of the triggers for the calorie restriction response to increase cell maintenance activities is based on nutrient sensing that is specific to methionine. Low methionine diets are perhaps more challenging to organize than the practice of calorie restriction, however. Researchers here offer an interesting alternative, which is to use an enzyme to break down methionine in the diet before it has the chance to enter the body. That enzyme can be delivered directly in the diet or, intriguingly, manufactured by bacteria that are introduced to the gut microbiome.

Obesity increases with aging. Methionine restriction affects lipid metabolism and can prevent obesity in mice. In the present study we observed C57BL/6 mice to double their body weight from 4 to 48 weeks of age and become obese. We evaluated the efficacy of oral administration of recombinant-methioninase (rMETase)-producing E. coli (E. coli JM109-rMETase) or a methionine-deficient diet to reverse old-age-induced obesity in C57BL/6 mice.

Fifteen C57BL/6 male mice aged 12-18 months with old-age-induced obesity were divided into three groups. Group 1 was given a normal diet supplemented with non-recombinant E. coli JM109 cells orally by gavage twice daily; Group 2 was given a normal diet supplemented with recombinant E. coli JM109-rMETase cells by gavage twice daily; and Group 3 was given a methionine-deficient diet without treatment.

The administration of E. coli JM109-rMETase or a methionine-deficient diet reduced the blood methionine level and reversed old-age-induced obesity with significant weight loss by 14 days. There was a negative correlation between methionine levels and negative body weight change. Although the degree of efficacy was higher in the methionine-deficient diet group than in the E. coli JM109-rMETase group, the present findings suggested that oral administration of E. coli JM109-rMETase, as well as a methionine-deficient diet, are effective in reversing old-age-induced obesity. In conclusion, the present study provides evidence that restricting methionine by either a low-methionine diet or E. coli JM109-rMETase has clinical potential to treat old-age-induced obesity.

A Seed and Soil Model for Gut Microbiome Aging to Contribute to Alzheimer's Disease
https://www.fightaging.org/archives/2023/07/a-seed-and-soil-model-for-gut-microbiome-aging-to-contribute-to-alzheimers-disease/

It is becoming clear that characteristic age-related changes in the composition of the gut microbiome accompany specific age-related diseases, and may well be contributing meaningfully to the development of those conditions. At the very least, the aged gut microbiome creates chronic inflammation, and that unresolved inflammatory signaling is disruptive to cell and tissue function throughout the body. There may be many other meaningfully involved mechanisms, however, such as changes in metabolite production. Many microbial metabolites have a beneficial effect on cell function, such as butyrate, and are known to decline with age.

The gut microbiota is critical for host protection against pathogens, immune development, and metabolism of dietary nutrients and drugs. In healthy individuals, the gut microbial composition is established early in life and remains relatively stable over time. Nevertheless, this ecosystem may become destabilized as a result of aging, environmental factors, and lifestyle habits such as diet. Shifts in gut microbial composition and diversity (i.e., gut dysbiosis) have been reported to influence neuroimmune and neuroendocrine functions through a bottom-up fashion resulting in neuroinflammation, microglial dysregulation, and aberrant protein aggregation in the Alzheimer's disease (AD) brain. Accordingly, this dysbiotic condition may set the stage for a toxic brain environment that stimulates AD neuropathophysiology, including the deposition of amyloid-beta (Aβ) plaques and neurofibrillary tangles.

The relationship between disruptions in the microbiota-gut-brain axis and AD can be explained by the Seed and Soil Model of Neurocognitive Disorders. Based on this model, the "seed" represents a predisposition to a neurocognitive disorder (e.g., genetic profile) and the "soil" refers to factors that moderate the expression of that seed. Together, the seed and the soil ultimately determine whether a person will develop the disorder. This model was created to explain why some people who are predisposed to develop neurocognitive disorders do not develop them. Although this model did not originally apply to the microbiota-gut-brain axis, the concept is general enough that it can be applied to many new contexts as ideas evolve.

In the case of AD and the microbiota-gut-brain axis, the seed could represent a polygenic risk score or family history of AD, whereas the soil could be represented by certain dysbiotic taxa. Dysbiotic taxa can contribute to many consequences including altered intestinal permeability that leads to a leaky gut and fosters the activation of local and distant immune cells. Given that the metabolites of gut leakiness are linked to increased permeability of the blood-brain barrier, these dysfunctions promote the translocation of bacterial endotoxins from the gut to the brain and increase inflammation within the system. According to the Seed and Soil Model of Neurocognitive Disorders, this translocation would create a toxic microenvironment in the brain vulnerable to pathogenesis, especially for those with a genetic predisposition to AD.

Consistent with this notion, a recent systematic meta-analysis showed that individuals with AD exhibited less gut microbial diversity than those with mild cognitive impairment (MCI) or healthy controls. Likewise, the gradient changes of abundance from normal cognition to MCI and AD stage were observed in several strains of gut microbiota (i.e., phylum Proteobacteria, family Clostridiaceae, and genus Phascolarctobacterium). Prior evidence also has revealed that gut-derived lipopolysaccharide (endotoxin) acts as an Aβ fibrillogenesis promoter, potentially leading to neuroinflammation and neurodegeneration.

Planarians Use a Similar Strategy to Embryonic Reprogramming to Maintain Immortality
https://www.fightaging.org/archives/2023/07/planarians-use-a-similar-strategy-to-embryonic-reprogramming-to-maintain-immortality/

There are a number of functionally immortal lower species, such as hydra, jellyfish, and planarians. Individual animals do not exhibit aging, in that mortality rate does not rise over time. An interesting question is the degree to which these species employ much the same strategy of cellular reprogramming as occurs in the early embryo of mammals, in order to maintain a youthful epigenome. Some of these species only maintain immortality under certain circumstances, and researchers have made use of that in order to examine what happens to cellular biochemistry when individuals switch from a state of aging to a state of rejuvenation and functional immortality.

An ability to delay aging or to reverse the negative effects of aging could prevent age-related disease and greatly enhance quality of life in old age. However, whether it is possible to globally reverse the physiological effects of aging in order to extend healthspan is unknown. The freshwater planarian Schmidtea mediterranea has been considered immortal due to its exceptional tissue regeneration capabilities. Here, we report that a sexually reproducing lineage of S. mediterranea exhibits age-associated physiological decline 12 months after birth. Age-associated changes include alterations in sensory organs, loss of neurons and muscle, loss of fertility, and impaired motility, but no reduction in stem cells at the age of 3 years.

Differential gene expression analysis, comparing young and old planarian cells, furthermore revealed cell-type-specific changes in transcription as well as changes in classical aging pathways (e.g., insulin signaling). Remarkably, amputation followed by regeneration of lost tissues led to a global reversal of these age-associated changes. Older individuals that underwent regeneration showed restored youthful patterns of gene expression, stem cell states, tissue composition and rejuvenation of whole-animal physiology. Our work reveals a naturally evolved solution to age reversal in planaria that may provide insights into anti-aging strategies in humans.

Mitochondrial Dysfunction as a Contribution to Muscle Aging
https://www.fightaging.org/archives/2023/07/mitochondrial-dysfunction-as-a-contribution-to-muscle-aging/

How much of the characteristic loss of muscle mass and strength that takes place with aging is the result of mitochondrial dysfunction? Mitochondria produce the chemical energy store molecules needed to power cellular processes, but in addition to the loss of this capacity, dysfunction in mitochondria can also generate oxidative stress that further impairs cell function. Some degree of mitochondrial dysfunction emerges from damage to mitochondrial DNA, but it is also the case that age-related changes in gene expression reduce the efficiency of mitochondrial quality control, the process of mitophagy responsible for removing damaged mitochondria. These processes are well investigated, and researchers are presently establishing ways to transplant mitochondria in large enough numbers to restore function throughout the body, but how great a benefit this systemic rejuvenation will produce has yet to be assessed in animal studies.

A hallmark of muscle aging is the buildup of dysfunctional and damaged mitochondria. However, the mechanisms leading to the accumulation of unhealthy mitochondria and whether this drives some of the aging-induced alterations are not fully understood yet. The process responsible for the selective degradation of damaged mitochondria, also known as mitophagy, is key in the maintenance of mitochondrial quality. Besides, mitophagy is tightly tuned with mitochondrial dynamics, and this coordination is essential during mitochondrial quality control. Indeed, alterations in these processes have been found to contribute to the accumulation of dysfunctional mitochondria in aged muscles.

In particular, we have shown that a reduction in the mitochondrial fusion protein Mitofusin 2 (Mfn2) during aging drives metabolic deterioration, muscle atrophy, and sarcopenia by a deregulation of mitochondrial dynamics and mitophagy. Interestingly, as a consequence of the accumulation of damaged and ROS-generating mitochondria, an adaptive mitophagy pathway involving ROS-induced expression of the mitophagy protein BNIP3 is activated in order to minimize mitochondrial damage. Pharmacological inhibition of this adaptive mitophagy pathway or genetic downregulation of muscle BNIP3 worsens mitochondrial quality and potentiates muscle atrophy. In contrast, re-expression of Mfn2 to levels comparable to those of young mice prevents muscle atrophy in old mice. Altogether, these data demonstrate a tight connection between mitochondrial health and the development of muscle atrophy and sarcopenia.

ATG4B Overexpression Increases Life Span in Flies
https://www.fightaging.org/archives/2023/07/atg4b-overexpression-increases-life-span-in-flies/

Researchers here show that increased expression of the autophagy regulator gene ATG4B improves health and extends life in flies, most likely via improved autophagy - though other mechanisms are involved, as is usually the case. Expression of the human version of ATG4B declines with age, and in humans long-lived individuals tend towards higher levels of expression. Autophagy is a maintenance process that clears out damaged proteins and structures.

A great deal of evidence points to the value of autophagy to long-term health, and to cellular stress responses in general, though the effect on life span in long-lived species seems to be much less impressive than is the case in short-lived species. In principle, more efficient clearance of damage leads to better cell and tissue function, but it is possible that cell maintance in long-lived species has already evolved to be much more efficient than is the case in short-lived species, leaving less room for benefits to be achieved via this sort of intervention.

Autophagy plays important but complex roles in aging, affecting health and longevity. We found that, in the general population, the levels of ATG4B and ATG4D decreased during aging, yet they are upregulated in centenarians, suggesting that overexpression of ATG4 members could be positive for healthspan and lifespan. We therefore analyzed the effect of overexpressing Atg4b (a homolog of human ATG4D) in Drosophila, and found that, indeed, Atg4b overexpression increased resistance to oxidative stress, desiccation stress and fitness as measured by climbing ability. The overexpression induced since mid-life increased lifespan.

Transcriptome analysis of Drosophila subjected to desiccation stress revealed that Atg4b overexpression increased stress response pathways. In addition, overexpression of ATG4B delayed cellular senescence, and improved cell proliferation. These results suggest that ATG4B have contributed to a slowdown in cellular senescence, and in Drosophila, Atg4b overexpression may have led to improved healthspan and lifespan by promoting a stronger stress response. Overall, our study suggests that ATG4D and ATG4B have the potential to become targets for health and lifespan interventions.

Lipid Droplet Accumulation in Aging and Age-Related Disease
https://www.fightaging.org/archives/2023/07/lipid-droplet-accumulation-in-aging-and-age-related-disease/

Researchers here consider dysregulation of lipid metabolism at the cellular level as an aspect of aging that causes downstream issues. Like many manifestations of aging observed in cells in aged tissues, why this happens is a matter for debate, setting aside situations such as the environment of a fatty liver or atherosclerotic plaque in which there is a localized excess of lipids to explain the overload inside cells. In a number of neurodegenerative conditions, the presence of cells loaded with lipid droplets is a prominent feature. It remains to be seen as to whether new classes of therapy under development, capable of clearing lipids in a selective manner, will prove to be useful in that context.

It is widely accepted that nine hallmarks - including mitochondrial dysfunction, epigenetic alterations, and loss of proteostasis - exist that describe the cellular aging process. Adding to this, a well-described cell organelle in the metabolic context, namely, lipid droplets, also accumulates with increasing age, which can be regarded as a further aging-associated process. Independently of their essential role as fat stores, lipid droplets are also able to control cell integrity by mitigating lipotoxic and proteotoxic insults.

As we will show in this review, numerous longevity interventions (such as mTOR inhibition) also lead to strong accumulation of lipid droplets in Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster, and mammalian cells, just to name a few examples. In mammals, due to the variety of different cell types and tissues, the role of lipid droplets during the aging process is much more complex. Using selected diseases associated with aging, such as Alzheimer's disease, Parkinson's disease, type II diabetes, and cardiovascular disease, we show that lipid droplets are "Janus"-faced. In an early phase of the disease, lipid droplets mitigate the toxicity of lipid peroxidation and protein aggregates, but in a later phase of the disease, a strong accumulation of lipid droplets can cause problems for cells and tissues.