Fight Aging! Newsletter, July 10th 2023

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.

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.

"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."

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.

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.

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.

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 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 (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.

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.

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.

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.

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.

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.

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.

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.