Fight Aging! Newsletter, January 18th 2021

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  • Targeting Neuroinflammation in Alzheimer's Disease
  • Looking Forward to the Longevity Industry in 2021
  • KAT7 Inhibition via Gene Therapy Reduces Cellular Senescence in the Liver and Extends Life in Mice
  • The 2020 Year End Fundraiser Brought in More than 2 Million for the SENS Research Foundation
  • A Few More Mammalian Species Found to Exhibit Amyloid-β and Tau Pathology
  • Suggesting Gum Disease Worsens the Progression of Other Conditions via Oxidative Stress Rather than Inflammation
  • Effects of Calorie Restriction on Cognitive Decline
  • Immunosenescence in Alzheimer's Disease
  • Thoughts on the Road to Greater Human Longevity
  • Predicting Alzheimer's Disease via Detection of Misfolded Amyloid-β in a Blood Sample
  • Targeting TGFβ to Treat Fibrotic Disease
  • Senescent Cells Provoke Excessive Sympathetic Nerve Fiber Growth, with Harmful Consequences
  • A Continued Focus on Metformin, a Demonstrably Poor Approach to Treating Aging
  • A Hypoxia Mimetic Drug Improves the Bone Marrow Environment to Treat Osteoporosis
  • Klotho Links Inflammation, Salt Sensitivity, Hypertension and Mortality in Aging

Targeting Neuroinflammation in Alzheimer's Disease

As noted by the authors of today's open access review paper, Alzheimer's disease is just as strongly characterized by chronic inflammation in brain tissue as it is by the presence of aggregates of amyloid-β and phosphorylated tau. More modern views of Alzheimer's disease etiology place more emphasis on chronic inflammation as a cause of pathology, either wrapping it into the amyloid cascade hypothesis, or replacing amyloid-β with inflammatory processes in the progression of the foundational, earlier stage of the condition.

The infection-senescence hypothesis, for example, suggests that persistent infection leads to cellular senescence in the supporting and immune cells of the brain (such as astrocytes and microglia), and senescent cells generate potent inflammatory signals that drive tau aggregation and the consequent widespread death of neurons. This view of senescent cells as agents of inflammation, that in turn provokes tau pathology, is supported by studies involving the use of senolytic therapies to clear senescent cells in the brains of mice engineered to produce tau aggregates. With senolytic treatment, all three metrics of senescent cell burden, chronic inflammation, and tau pathology are markedly reduced in these mouse models of tauopathy.

This sort of specific theorizing and experimentation on neurodegeneration and neuroinflammation is not happening in a vacuum. There is considerable interest in a wide range of strategies that might reduce chronic inflammation in the aging brain, and thereby slow or reverse the progression of neurodegenerative conditions. The evidence to date from work on senolytics suggests that some fraction of the declines of old age are actively maintained by inflammatory signaling, and reverse themselves quite rapidly when that signaling is suppressed (such as by removal of senescent cells). The situation in the brain may be much the same as that elsewhere in the body, even accounting for the poor regenerative capacity of central nervous system tissue.

Can We Treat Neuroinflammation in Alzheimer's Disease?

Neuroinflammation is a process regulated by brain resident macrophages, the microglia cells, which are required to recognize and eliminate any toxic component in the central nervous system (CNS). Microglia has a high capacity for mobility, and they can switch between two different phenotypes, M1 and M2, characterized by a different morphology and cytokine profile. The M2 phenotype is the resting type that actively monitors the brain in healthy conditions. The switch to M1 begins with the recognition of the pathogen-associated molecular patterns (PAMPs) or the damage-associated molecular patterns (DAMPS) by the pattern recognition receptors (PRRs).

Pro-inflammatory cytokines purpose is to orchestrate the neutralization and elimination of toxic molecules and/or cellular debris. In normal conditions, once the toxic stimuli have been cleared, microglia swifts to the anti-inflammatory (M1) phenotype and secretes anti-inflammatory cytokines, brain-derived neurotrophic factor (BDNF), or nerve growth factor (NGF), whose role is to terminate the innate immune response and contribute to restore the synaptic function. However, under pathological conditions, microglia cells do not go back to their resting state, thus causing a chronic inflammation process, with the overproduction of pro-inflammatory cytokines and reduction of neuroprotective factors that in sustained situations become highly toxic, leading to neurodegeneration. Therefore, the chronic neuroimmune system activation underlies the initiation and progression in many dementias, and surely, is involved in late onset of AD. Not only amyloid-β activates the microglia, but also misfolded Tau interaction with microglia triggers inflammation.

Neuroinflammation and insulin resistance are considered major neuropathological events underlying the onset and progression of AD; therefore, multiple strategies that target these processes have been developed to effectively treat this disease. In the current review, we have revised some of the latest preclinical and clinical studies targeting inflammation in AD, either directly with anti-inflammatory drugs or indirectly, improving insulin signaling. Taking together all clinical studies revised, we conclude that strategies targeting neuroinflammation together with insulin resistance have, finally, demonstrated to be a promising therapeutic potential in Alzheimer's disease, especially at early stages. However, many molecules have produced inconclusive results, and other methods, such as promoting neuroprotection via CB2 boosting or restoring a more youthful gut microbiome, are still at the preclinical stage. In addition, patient's stratification seems to be crucial to determine best treatment. The definite cure for AD does not exist yet; however, targeting neuroinflammation may be a path worth pursuing.

Looking Forward to the Longevity Industry in 2021

Having written retrospectives for 2020, longevity industry observers are now looking forward to what we might expect in 2021. This survey of companies and projects in the longevity industry is unbiased from the point of view of whether or not the treatments under development are expected to have a sizable effect on human aging. Can they slow aging or actually reverse aging meaningfully? It is more focused on progress on startups, business matters, and potential for profit.

One of the many issues with the highly regulated medical development market is that success in investment is only somewhat connected to success in generating a therapy. Liquidity events for investors in early stage biotech companies occur well before clinical approval by regulators, and thus incentives are not completely aligned. Merely fleshing out animal data and applying hype to a given mechanism (see the Sitris Pharmaceuticals story, for example) can work just as well as actually setting out to build a viable therapy that can have sizable effects on aging, when it comes to giving investors a sizable return on investment.

Further, the market values (a) incremental, modest advances that are easier to explain to regulators, and that fit in existing frameworks for evaluation over (b) radical, ambitious advances based on entirely new approaches that will require greater effort to obtain approval. In the treatment of aging as a medical condition, we need those radical, ambitious advances. The incremental, modest advances (such as yet another way to mimic calorie restriction, as if we need more of those) are not going to move the needle all that much on human life span. People will still be aging and dying in much the same way as their parents and grandparents did.

Top 10 Things to Watch in the Longevity Industry in 2021

Jim Mellon, billionaire patron saint of longevity investing, announced in September 2020 that he would take his longevity portfolio company, Juvenescence, public within 6-12 months. Juvenescence's diversified portfolio of 11 assets spans the gamut of senolytics, AI companies, regenerative medicine, and nutraceutical products. The Juvenescence IPO will be the biggest development in public market longevity investing since Unity Biotechnology went public in 2018. And because Juvenescence is a diversified portfolio of longevity companies it best represents the entire industry going forward.

Kristen Fortney's AI / computational drug discovery company BioAge recently closed a Series C round and will use the funds to initiate Phase 2 clinical trials this year. BioAge uses AI, machine learning, and systems biology models to mine multi-omics patient datasets and identify existing drugs that are likely to treat age-related disease. Since BioAge's strategy is to repurpose existing drugs they are able to go straight to Phase 2 trials.

Nir Barzilai recently gave an online talk with the Foresight Institute. In the talk he mentioned that an unnamed wealthy individual was in the process of setting up a longevity foundation that would invest 1 billion into anti-aging research and companies per year. Barzilai said the foundation would be announced in January of this year. Who could be the mysterious donor? Nir Barzilai indicated it is the same mysterious person that is funding the TAME trial and is a well known tech billionaire. My guess: It's Larry Ellison, founder of Oracle. He has a net worth of 88 billion and is 76 years old. Ellison has also donated to longevity causes in the past through the Ellison Medical Foundation. My second guess is Sergey Brin of Google.

2020 was a disastrous year for Unity Biotechnology. But 2021 could be a year of redemption for Unity. Their new Phase 1 trial for UBX1325, a Bcl-xL inhibitor to treat Diabetic Macular Edema (DME), will be completed in the first half of this year, with a proof of concept trial to follow shortly afterwards. I am cautiously optimistic for Unity Biotechnology. But I am also totally unworried if they fail, as there are many many other senolytics companies preparing for clinical trials - many with 2nd generation targeted approaches that may prove superior to Unity's.

2021 will be the year that more senolytics companies finally join Unity in the clinical race. And many of these companies are using 2nd gen targeted approaches to clear senescent cells. FoxBio, a Juvenescence and Ichor Therapeutics senolytics joint venture, is planning Phase 1 trials for an osteoarthritis drug this year. Numeric Biotech, a spin out from Erasmus Medical Center in the Netherlands, is planning to test the FOXO4-DRI peptide. Senolytic Therapeutics, one of David Sinclair's Life Biosciences daughter companies, has two mature assets that should be close to ready for clinical trials - although there is no set date.

KAT7 Inhibition via Gene Therapy Reduces Cellular Senescence in the Liver and Extends Life in Mice

Since the confirmation of cellular senescence as an important contributing cause of aging, a great many research initiatives have focused on the biochemistry of senescent cells, in search of new approaches to rejuvenation therapies. A common strategy in the life sciences is to deactivate genes one by one and observe the results, in search of suitable regulators to change cell behavior. In today's open access paper, researchers report on the results of such a screen of gene functions, identifying KAT7 as a gene important in the regulation of cellular senescence in at least the liver.

The researchers screened for gene function in cell cultures, but they used gene therapy in mice to demonstrate that KAT7 knockdown via CRISPR methods reduces cellular senescence in the liver, improves liver function, and extends mouse life span. They did not comment on other organ systems. The liver is the focus of this study most likely because it is the easiest organ to target via present gene therapy vectors. Something like 80% to 90% of any vector that is injected intravenously will end up in the liver. It is not completely clear how KAT7 reduces senescence, whether it is involved in more efficient destruction of senescent cells, or lowers the number of cells that become senescent in response to damage or signaling.

The question with all novel approaches to reducing the burden of senescence is whether they will do more harm than good - which is why it is important to check on longer term health and life span outcomes when conducting animal studies. Selectively destroying senescent cells is confirmed to be beneficial, increasing mouse health and life span. Preventing cells from becoming senescent, on the other hand, is beneficial in the short term, lowering the burden of inflammatory signaling generated by senescent cells, but could in principle raise the risk of cancer and other issues in the longer term, by allowing damaged cells to continue replicating. In the KAT7 work, the treated mice lived longer, an interesting outcome.

A genome-wide CRISPR-based screen identifies KAT7 as a driver of cellular senescence

Cellular senescence, a state of permanent growth arrest, has recently emerged as both a hallmark of aging and a fundamental driver of the aging processes. Senescent cells accumulate in tissues over time, triggering natural features of organismal aging and contributing to aging-related diseases (for example, hepatic steatosis and osteoarthritis). Prophylactic ablation of senescent cells expressing the senescence marker p16INK4A mitigates tissue degeneration and extends the health span in mice, indicating that senescent cells play a causative role in organismal aging. For example, senescent cells gradually accumulate in the degenerated liver, whereas clearing senescent cells from the liver attenuates the development of hepatic steatosis.

Understanding the genetic and epigenetic bases of cellular senescence is instrumental in developing interventions to slow aging. We performed genome-wide CRISPR-Cas9-based screens using two types of human mesenchymal precursor cells (hMPCs) exhibiting accelerated senescence. The hMPCs were derived from human embryonic stem cells carrying the pathogenic mutations that cause the accelerated aging diseases Werner syndrome and Hutchinson-Gilford progeria syndrome. Genes whose deficiency alleviated cellular senescence were identified, including KAT7, a histone acetyltransferase, which ranked as a top hit in both progeroid hMPC models.

Inactivation of KAT7 decreased histone H3 lysine 14 acetylation, repressed p15INK4b transcription, and alleviated hMPC senescence. Moreover, lentiviral vectors encoding Cas9/sg-Kat7, given intravenously, alleviated hepatocyte senescence and liver aging and extended life span in physiologically aged mice as well as progeroid Zmpste24-/- mice that exhibit a premature aging phenotype. KAT7 may represent a therapeutic target for developing aging interventions.

The 2020 Year End Fundraiser Brought in More than 2 Million for the SENS Research Foundation

The SENS Research Foundation represents the best of charitable organizations working on the treatment of aging as a medical condition. It is well run, focuses on approaches capable of rejuvenation rather than merely modestly slowing aging, devotes funds and attention towards those projects in rejuvenation research that most need support in order to advance, and has a great track record when it comes to helping development programs to make the leap from academic laboratories to commercial development in startup biotech companies.

The SENS Research Foundation is near entirely supported by philanthropy, including the donations of a community of thousands of everyday visionaries, people just like you and I who want to see meaningful progress towards therapies capable of sizable degrees of human rejuvenation. For some years now, the SENS Research Foundation has run an annual year end fundraiser, bringing in millions in funding. Those funds were used well in helping to advance the state of the art in rejuvenation research.

On that topic, I'm pleased to note that last year's fundraiser, concluding a few short weeks ago, succeeded in raising more than 2 millon to help fund the rejuvenation-focused projects of 2021. From the latest SENS Research Foundation newsletter:

SENS Research Foundation supporters, thank you for going above and beyond with your generosity, especially at the end of such a difficult year. Your commitment to helping #UnlockLongevity brought in $2,355,443.46 - more than doubling our end of year campaign fundraising goal of $1M! Special thanks to Michael Antonov, Brendan Iribe, Karl Pfleger, Jim Mellon, Cameron Bloomer, Dave Fisher, Christophe Cornuejols, Didier Coeurnelle, and Larry Levinson for their matching grants during the campaign, as well as to all of you who donated at every level.

Your support means SENS Research Foundation can hit the ground running as we start 2021, with exciting research progress, facility upgrades, and more on the horizon. It means so much to us to have a community behind us that truly shares our vision of a world free of age-related disease, and is willing to help do what it takes to make such a world a reality sooner rather than later.

A Few More Mammalian Species Found to Exhibit Amyloid-β and Tau Pathology

The primary challenge in Alzheimer's disease research has long been that short-lived laboratory species do not naturally exhibit any of the features of the condition. Thus all mouse models of the condition are highly artificial genetic constructs, and potential treatments and relevant mechanisms in these models have a high chance of being irrelevant to Alzheimer's disease as it exists in humans. Up until fairly recently it could be argued that humans were in fact the only species to exhibit full blown Alzheimer's disease, involving a lengthy increase in amyloid-β aggregation in the brain, followed by neuroinflammation, tau aggregation, and widespread cell death.

However, in recent years the study of chimpanzee brains - as well as a variety of other species - suggests that some might exhibit enough of the mechanisms of Alzheimer's disease to be said to suffer from it in old age. This is also the case in the aging of dolphins. In today's open access paper, researchers report on more signs of Alzheimer's mechanisms in the brains of sea lions, seals, and walrus. This is all interesting, but doesn't much help the state of Alzheimer's research in practice. None of these large mammal species are likely to be used in laboratories any time soon. Even if they were, it would not be for early stage discovery and exploration.

Amyloid β and tau pathology in brains of aged pinniped species (sea lion, seal, and walrus)

Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disorder and is characterized by the pathological aggregation of the amyloid-β (Aβ) and hyperphosphorylated tau (hp-tau) proteins in the form of senile plaques (SPs) and neurofibrillary tangles (NFTs), respectively. The accumulation of Aβ in the blood vessels of the brain, a condition known as cerebral amyloid angiopathy (CAA), is also detected in more than 80% of patients with AD. Humans appear to be uniquely susceptible to AD, potentially due to genetic differences, changes in cerebral structures and functions during evolution, and an increased lifespan. In the "amyloid hypothesis", the most acknowledged explanation for the pathogenesis of AD, the age-dependent accumulation of fibrillar insoluble Aβ peptides in the brain is considered to be the central and triggering event in AD pathology. Based on this hypothesis, various transgenic mouse models that produce human Aβ beyond physiological levels have been generated and exhibit the massive formation of SPs. However, they fail to develop NFTs and neuronal loss unless mutant tau is simultaneously introduced.

While AD appears to be a human-specific disease, age-dependent SP formation has been reported in several non-human primates, including chimpanzees, orangutans, and gorillas. The concomitant pathology with the formation of a small amount of NFTs was found in chimpanzees and rhesus macaques, while the oligodendroglial tau pathology was also detected in cynomolgus monkeys. Therefore, an AD-like pathology may occur during aging in primates. In contrast, non-primate animals, particularly Carnivora species, have exhibited species-specific patterns of Aβ and hp-tau accumulation. In the suborder Caniformia, aged dogs and bears developed SPs in their brains, but not NFTs, even in the oldest subjects. On the other hand, Feliformia species, such as cats, leopard cats, and cheetahs, exhibit NFTs without SP formation, although small granular deposits of Aβ were detected in the cerebral cortex.

Pinnipeds are semiaquatic carnivorans that spend most of their lives in water, and use coastal terrestrial environments and ice packs to breed, molt, and rest. They are currently classified into three families: Phocidae (seals), Otariidae (fur seals and sea lions), and Odobenidae (walruses). We herein describe the Aβ and hp-tau pathology in the brains of aged pinniped species. Molecular analyses revealed that the sequence of pinniped Aβ was identical to that of human Aβ. Histopathological examinations detected argyrophilic plaques composed of Aβ associated with dystrophic neurites in the cerebral cortex of aged pinnipeds. Astrogliosis and microglial infiltration were identified around Aβ plaques. Aβ deposits were observed in the blood vessel walls of the meninges and cerebrum.

Histopathological examinations revealed that argyrophilic fibrillar aggregates composed of phosphorylated tau (hp-tau) in the neuronal somata and neurites of aged pinniped brains. Furthermore, the activation of GSK-3β was detected within cells containing hp-tau aggregates, and activated GSK-3β was strongly expressed in cases with severe hp-tau pathologies. The present results suggest that, in association with Aβ deposition, the activation of GSK-3β contributes to hp-tau accumulation in pinniped brains.

Suggesting Gum Disease Worsens the Progression of Other Conditions via Oxidative Stress Rather than Inflammation

Periodontitis, gum disease, produces chronic inflammation that is thought to worsen the progression of conditions such as cardiovascular disease and dementia, through the size of the effect is debated. Certainly there are good reasons to believe that more chronic inflammatory signaling is worse than less chronic inflammatory signaling. Researchers here suggest that the observed relationship between periodontitis and progression of chronic kidney disease is mediated by excessive production of oxidative molecules rather than by inflammation.

Previous studies have shown a link between the severe oral inflammation caused by gum disease and chronic kidney disease (CKD) which demonstrated that those with worse inflammation of the gums have worse kidney function. Previous research also showed that patients with CKD and periodontitis experience a drop in survival rates, similar in magnitude to if they had diabetes instead of gum inflammation, suggesting that gum inflammation may casually affect kidney function.

In this latest study, over 700 patients with chronic kidney disease were examined using detailed oral and full-body examinations including blood samples. The aim was to test the hypothesis that periodontal inflammation and kidney function affect each other and to establish the underlying mechanism that may facilitate this. Results showed that just a 10% increase in gum inflammation reduces kidney function by 3%. In this group of patients, a 3% worsening in kidney function would translate to an increase in the risk of kidney failure over a 5 year period from 32%-34%. Results also showed that a 10% reduction in kidney function increases periodontal inflammation by 25%.

In contrast to current beliefs that inflammation is the link between periodontitis and other systemic diseases, researchers found that in this group of patients the effect was caused by a biological process called "oxidative stress" - or, an imbalance between reactive oxygen species and the body's antioxidant capacity which damages tissues on a cellular level.

Effects of Calorie Restriction on Cognitive Decline

The practice of calorie restriction slows aging and extends healthy life, quite dramatically so in short-lived species, and far more modestly in long-lived species. All of the mechanisms of aging, the forms of damage that accumulate in old tissues and the outcomes of that damage, are affected. Some are affected more than others, however. So it is possible to see some aspects of aging that are less robustly responsive to calorie restriction, such as loss of cognitive function, as noted here.

It is interesting to speculate on the specific mechanisms involved in an age-related decline that responds well to life-long calorie restriction, but very poorly to calorie restriction initiated in later life. We know for example that structural damage to the brain occurs in conjunction with vascular aging, meaning increased blood pressure, reduced integrity of the blood-brain barrier, and so forth. The brain regenerates poorly, so this is a form of damage that accumulates over time and will not be remediated by a later adoption of calorie restriction and a corresponding reduction in blood pressure.

Calorie restriction (CR) has been considered the most effective non-pharmacological intervention to counteract aging-related diseases and improve longevity. This intervention has shown beneficial effects in the prevention and treatment of several chronic diseases and functional declines related to aging, such as Parkinson's, Alzheimer's, and neuroendocrine disorders. However, the effects of CR on cognition show controversial results since its effects vary according to intensity, duration, and the period of CR.

Here we present some of the results of the last ten years of studies with CR at different stages of life on neurodegenerative diseases such as Alzheimer's disease. Some investigations associating CR with physical exercise have also been presented. Together this association is the main non-pharmacological strategy to prolong longevity and quality of life. We also presented some substances that mimic the effects of CR and would be potential drugs to mimic the beneficial effects of CR in individuals with some restrictions on intervention. Several studies have also been carried out not only in conventional laboratory animals but also in some wild models since CR can be an environmental factor that interferes with the survival and perpetuation of species.

This information can show the different effects of CR on cognition depending on the period in which it is initiated, its intensity and duration in different animal models, and how it can interfere with the quality of life of individuals. These studies contribute to a better understanding of the mechanisms related to CR in cognition and support future studies with humans. CR may be a potential alternative to the treatment of comorbidities related to mental healthy and cognition.

We conclude that CR between 20% and 40% initiated in the first month of life would attenuate age-related cognitive declines in experimental animals, in healthy and pathological aging, such as in Alzheimer's disease. CR may not reverse the harmful effects of aging on cognition if starts later. In addition, CR also attenuates cognitive deficits resulting from obesity and brain injuries such as traumatic brain. Finally, CR can improve cognition, when performed with moderate intensity and early in life. When performed intensely and later in experimental animals, CR may be deleterious for cognition.

Immunosenescence in Alzheimer's Disease

Researchers here catalog the various mechanisms known to be involved in the development of Alzheimer's disease that occur as a result of the aging of the immune system. The immune system becomes less effective with age, but also constantly overactive. It generates constant and unresolved inflammatory signaling that damages tissue structure and disrupts tissue function. All of the common age-related conditions are accelerated and worsened by the chronic inflammation resulting from the age-damaged immune system.

Alzheimer's disease (AD) is the most common type of dementia characterized by progressive memory loss, visual-spatial impairment, executive dysfunction, and personality and behavioral changes. The pathological features of AD are neuritic plaques, neurofibrillary tangles, neuronal and synaptic loss, and the activation of microglia. Over the past few decades, the amyloid cascade hypothesis has dominated the field of AD research, suggesting that amyloid-β (Aβ) deposition is the central event in AD pathology. However, recent findings have challenged this hypothesis and argue that Aβ protects the brain from infection, and its aggregation promotes microglia-mediated neuroinflammation. The viewpoint that altered immune and inflammatory responses may play the main role in the progression of AD has increasingly been recognized.

In recent years, research is making significant progress and proposes that immunosenescence actively participates in the pathogenesis of AD and mediates inflammatory damage. Microglia are innate immune cells that reside in the brain and play an important role in maintaining homeostasis and immune defense. Microglia undergo significant changes in the aging brain. Morphologically, aged microglia exhibit cytoplasmic hypertrophy and branch reduction. Functionally, senescent microglia show higher proliferative capacity and production of proinflammatory cytokines, but reduced chemotaxis and ability to clear Aβ. Activated and proliferated microglia surround amyloid plaques in the AD brain and participate in the clearance of Aβ. Aβ binds to TLRs, RAGE, and other receptors on the surface of microglia membranes, transducing intracellular signaling pathways, then leading to the synthesis and release of pro-inflammatory factors. In the aging brain, the phagocytic capacity of microglia is weakened, which leads to the accumulation of Aβ. Microglia continue to activate, leading to chronic inflammation, increased oxygen free radicals, mitochondrial damage, and ultimately neuronal death.

Inflammation, a normal repair response, is crucial to combat pathogens and clear dead cells. Once the inflammation is dysregulated, it will cause tissue damage. Inflammaging refers to a state of chronic pro-inflammatory response in the process of aging, which is considered to be a part of immunosenescence. AD is also considered to be a chronic inflammatory disease. The inflammatory response of AD is not limited in the brain, but also exists in peripheral tissues, which is considered to be part of the systemic inflammatory response. The chronic inflammatory state in aging individuals may be associated with long-term chronic microbial infections, which may be a driver of cognitive decline and possibly dementia in the elderly.

Thoughts on the Road to Greater Human Longevity

I recently noticed this scientific commentary, published in a journal not specifically focused on aging. The author is far from the only person to have noticed that priorities in medical research and development do not seem to match up with the major causes of death all that well. It can't hurt to keep on pointing out that research into the most harmful biological processes in the world, meaning the mechanisms that cause aging, is very poorly funded and investigated in comparison to the vast and ongoing toll of death that results. Until aging is defeated, more funding for research into rejuvenation therapies will continue to be the most cost-effective way to improve the human condition.

Longevity means living a long life, nowadays often considered a life span over 85 to 100 years. More and more people reach this limit in modern welfare societies, and citizens aged 90 years and over are said to be the fastest increasing group of people. This is a reality, but what are the background factors for this development? Many scholars think that it is mostly due to societal factors like improved hygiene, proper diet and safer environment. These are important but have mainly established the sine qua non for reaching old age through living past dangerous childhood and earlier adult life and becoming old. In modern societies, reaching longevity is jeopardized more by chronic non-communicable diseases which have replaced infectious diseases as primary causes of morbidity and mortality. By the way, according to the Global Health Estimates by the World Health Organization, during the first half of 2020, non-communicable diseases killed approximately 25 times more people than the ongoing COVID-19 pandemic.

According to the Bible, 'The days of our years are threescore years and ten (70 years); and if by reason of strength they be fourscore years (80 years), yet is their strength labour and sorrow; for it is soon cut off...'(Psalm 90:10). This well accords with the thoughts of biogerontologists: the warranty period of homo sapiens is 65 years, where after on the average 20 years can be attained, mainly depending on life-course factors. Whilst age 85 years is an upper limit to life expectancy at the population level, ca. 40% of the original birth cohort nevertheless can reach 90 years, 5-6% 100 years, few 100-115 years, and only a handful of individuals over that.

The most common non-communicable diseases are cardiovascular diseases, chronic obstructive pulmonary diseases, cancer, and degenerative diseases. Many risk factors for them have been identified. Overall, it seems feasible that health span - healthy years of life - extension and successful ageing can be promoted with better and long-term cardiovascular risk factor control. However, for reaching 100 years and over the role of genetic factors affecting longevity strengthens. For most of the population, extending life span and especially health span over 90 years requires new methods to control the biological ageing processes, currently investigated in the realms of Geroscience, the Longevity Dividend, and the Global Roadmap for Healthy Longevity.

Predicting Alzheimer's Disease via Detection of Misfolded Amyloid-β in a Blood Sample

The research community is making progress towards forms of low cost testing for Alzheimer's disease risk. At present, the well established tests are invasive or expensive. The very early stages of Alzheimer's disease, in which symptoms are mild or absent, are characterized by increasing levels of amyloid-β in the brain. However, amyloid-β in the brain is in a state of dynamic equilibrium with amyloid-β in the bloodstream, and in principle a suitable sensitive test can use a blood sample to assess the relevant aspects of amyloid-β burden. It takes years to validate predictions of Alzheimer's risk of course, and here researchers report on a lengthy but successful validation of one particular blood sample assay.

Using a blood test, a research team has predicted the risk of Alzheimer's disease in people who were clinically diagnosed as not having Alzheimer's disease but who perceived themselves as cognitively impaired. The cohort included 203 individuals. Using a test called the Immuno-Infrared Sensor, they identified all 22 subjects at study entry who developed Alzheimer's dementia, thus the clinical symptoms, within six years.

At study entry, blood samples were taken from all the participants and analyzed using the patented immuno-infrared sensor that detects misfolding of the amyloid-beta (Aβ) peptide, which is a biomarker for Alzheimer's disease. In addition, the subjects underwent extensive Alzheimer's disease diagnostic testing; at study entry, this did not provide a diagnosis of Alzheimer's disease in any of the subjects studied. The immuno-infrared sensor, on the other hand, detected misfolded Aβ peptides at study entry in all 22 subjects who developed the clinical disease in the following six years. In subjects who showed mild misfolding, it took on average longer (3.4 years) for conversion to clinical Alzheimer than in subjects with severe Aβ misfolding (2.2 years).

In addition, the team checked whether the combination of two different measurement methods in the plasma biomarker panel could further improve the prediction of disease risk. For this purpose, they combined the misfolding of all Aβ isoforms with a concentration decrease for Aβ42 as ratio to Aβ40 in plasma. This increased the assay accuracy. Such a blood test, which can detect the onset of Alzheimer's dementia even in the asymptomatic state, would be particularly useful if a drug were available to treat the disease.

Targeting TGFβ to Treat Fibrotic Disease

TGFβ is an important component of the inflammatory signaling of senescent cells, and cellular senescence is involved in the progression of numerous fibrotic and age-related conditions. Chronic inflammation causes tissue maintenance processes to run awry, and fibrosis, the inappropriate deposition of scar-like collagen structures that disrupt tissue function, is one of the possible outcomes. Here, researchers use an established class of compound to target this form of inflammatory signaling, finding that the treatment has a positive impact on fibrotic disease in animal models. This is consistent with other studies that have found that TGFβ is a useful target, in that suppressing TGFβ signaling can limit the harms done by senescent cells.

Fibrotic disease is a major cause of mortality worldwide, with fibrosis arising from prolonged inflammation and aberrant extracellular matrix dynamics. Compromised cellular and tissue repair processes following injury, infection, metabolic dysfunction, autoimmune conditions, and vascular diseases leave tissues susceptible to unresolved inflammation, fibrogenesis, loss of function and scarring.

There has been limited clinical success with therapies for inflammatory and fibrotic diseases such that there remains a large unmet therapeutic need to restore normal tissue homoeostasis without detrimental side effects. We investigated the effects of a newly formulated low molecular weight dextran sulfate (LMW-DS), termed ILB, to resolve inflammation and activate matrix remodelling in rodent and human disease models. We demonstrated modulation of the expression of multiple pro-inflammatory cytokines and chemokines in vitro together with scar resolution and improved matrix remodelling in vivo.

Of particular relevance, we demonstrated that ILB acts, in part, by downregulating transforming growth factor (TGF)β signalling genes and by altering gene expression relating to extracellular matrix dynamics, leading to tissue remodelling, reduced fibrosis, and functional tissue regeneration. These observations indicate the potential of ILB to alleviate fibrotic diseases.

Senescent Cells Provoke Excessive Sympathetic Nerve Fiber Growth, with Harmful Consequences

Senescent cells are created constantly throughout life in response to a range of circumstances, but only begin to accumulate in later life, once there is an imbalance between processes of creation (as a response to cell damage, for example) and processes of destruction (such as immune surveillance of senescent cells). Senescent cells secrete a potent mix of signals that, when sustained over time, provokes chronic inflammation and alters nearby cell behavior and tissue structure in detrimental ways. Researchers are only now attempting to catalog exactly how senescent cells cause harm, given the advent of senolytic therapies that allow a good assessment of the degree to which senescent cell accumulation contributes to specific degenerative processes in aging.

The sympathetic nervous system (SNS) is involved in a multitude of biological phenomena including stress, energy utilization, and physical activity; crucial physical functions that are regulated by the SNS include hemodynamics, temperature regulation, and metabolism. Overactivity of the SNS can result in types of chronic diseases, including cardiovascular disorders and hypertension. Multiple lines of evidence have demonstrated that sympathetic nerve density increases in tumor tissues.

Cellular senescence is implicated in several lines of aging-related disorders. However, the potential molecular mechanisms by which cellular senescence modulates age-related pathologies remain largely unexplored. Herein, we report that the density of sympathetic fibers (SFs) is significantly elevated in naturally aged mouse tissues and human colon adenoma tissues compared to the SFs densities in the corresponding young mouse tissues and human non-lesion colon tissues.

A dorsal root ganglion (DRG) and human diploid fibroblast co-culture assay revealed that senescent cells promote the outgrowth of SFs, indicating that the senescent cells induce recruitment of SFs in vitro. Additionally, subcutaneous transplantation of fibroblasts in nude mice shows that transplanted senescent fibroblasts promote SFs infiltration. Intra-articular senolytic molecular injection can reduce SFs density and inhibit SFs infiltration caused by senescent cells in osteoarthritis (OA), suggesting senescent cells promote the infiltration of SFs in vivo in aged tissues. Notably, the elevated level of SFs contributes to impaired cognitive function in naturally aged mice, which can be reversed by treatment with propranolol hydrochloride, a non-selective β receptor blocker that inhibits sympathetic nerve activity (SNA) by blocking non-selective β receptors.

Taken together, this study concludes that senescent cells secrete netrin-1 that mediates SFs outgrowth and infiltration, which contributes to aging-related disorders. This suggests that clearing senescent cells or inhibiting SNA is a promising therapeutic strategy for improving sympathetic nervous system (SNS) hyperactivity-induced aging-related pathologies.

A Continued Focus on Metformin, a Demonstrably Poor Approach to Treating Aging

Metformin is a poster child for the way in which much of the aging research community is focused on approaches to aging that cannot possibly achieve more than a very modest slowing of degeneration, and where the existing evidence strongly suggests that those tiny positive outcomes will be unreliable at best. Metformin is a way to tinker with the operation of a damaged metabolism, not a way to repair that damage. As a calorie restriction mimetic, the animal data shows that it compares very poorly to calorie restriction itself. We know that calorie restriction doesn't do anywhere near enough for human longevity. This is not the way forward to human rejuvenation.

Although current research gives promise to metformin as an anti-aging drug, there are still concerns that need to be highlighted, and they apply not only to research into metformin but to other anti-aging mechanisms and drug research as well. First, despite the positive outcomes from many studies, it is not uncommon to find a change in dosage turning the result from life-extending to life-ending. When a low dose of metformin (0.1%) was given to middle-aged male mice with their diet, their lifespans were extended by 5.83% on average, but a higher concentration (1%) became toxic.

Another issue standing in the way relates to the side effects associated with chronic use of drugs. About 25% of patients treated with metformin have gastrointestinal side effects. Besides, chronic use of metformin can cause dose-dependent vitamin B12 deficiency, increasing the risk for anemia and neuropathy. Future research should also work to elucidate how gender influences drug effectiveness. Metformin increased mean lifespan of female mice by 4.4% while decreasing that of male mice by 13.4%. Male pre-diabetic patients who received metformin had a significantly lower coronary calcium score compared with control, while the female group did not.

The issues of dosage, side effects, sexual dimorphism, and genetic regulatory mechanisms all point to the need for large-scale clinical trials. The Metformin in Longevity Study (MILES) involved 14 older than 70 year-old people who were randomized to take metformin and placebo in either order each for six weeks with a two-week washout period in between. As the number of subjects was small and the duration short, MILES effectively revealed many transcriptomic and metabolomic changes in the muscle and adipose tissue. The Glucose Lowering In Non-diabetic hyperglycaemia Trial (GLINT) is intended to evaluate the performance of metformin in reducing CVD risks by following 20,000 hyperglycemic but non-diabetic patients for five years. A one-year feasibility RCT enrolling 249 elderly, obese, and with high CVD risk (mean 28.8%, SD 8.5%) participants was concluded in 2018, and metformin improved several CVD risk indicators and decreased vitamin B12 levels. However, it also revealed problems such as a high rate of trial discontinuation (30% by six months).

The Targeting Aging with Metformin (TAME) trial is a large placebo-controlled trial that is designed to enroll 3000 subjects to test whether metformin delays age-related diseases. The TAME trial received FDA approval in 2015, and after receiving all the required budget in 2019, it was set to start at the end of the same year. The TAME trial may make metformin the first approved drug for anti-aging, but, more importantly, since it is not testing metformin against a single disease but a collection of age-related ones, it establishes aging as a medical condition that can be intervened or treated instead of an irreversible process outside human control. The shift in the notion of aging will enable future anti-aging clinical to trials proceed with much more ease.

A Hypoxia Mimetic Drug Improves the Bone Marrow Environment to Treat Osteoporosis

Researchers here show that an iron chelation drug (deferoxamine, brand name desferal) triggers a portion of the cellular reaction to hypoxia in bone marrow. Hypoxia is one of the many types of stress that, when mild, induces cells to greater efforts in maintenance and repair, resulting in a net gain in cell function. In the rats treated with deferoxamine in this study, the hypoxia mimetic acts to reduce the burden of cellular senescence, and otherwise shift the behavior of cells in the direction of slowing the onset of osteoporosis.

Bone marrow stromal cells (BMSCs) exist in the bone marrow with multi-potency and have a broad application prospect in the field of cell therapy and regenerative medicine thanks to their accessibility and expansion potential. Previous study showed a high potential association between BMSC senescence and age-related bone loss. Several studies have documented that age drives the intrinsic alterations of BMSCs, including decreased proliferation and osteogenic differentiation potential, as well as increased senescence-associated gene expression and β-galactosidase-positive staining. It also reported that the viability of aged BMSCs decreased, and senescent BMSCs were more likely to differentiate into adipocytes. These changes led to the decrease in quantity and quality of BMSCs, which together contributed to age-related bone loss.

Oxygen is a fundamental element of the bone marrow niche, and a hypoxic environment in the bone marrow is generally considered to be indispensable for retaining normal physiological function and self-renewal of stromal cells. As the key transcription factor response to hypoxia stress, hypoxia-induced factor 1α (HIF-1α) is a highly unstable protein in normoxic conditions. However, under hypoxic conditions, the catalytic activity of prolyl hydroxylases (PHD) is inhibited, leading to the stabilized expression of HIF-1α. Some small molecules, such as deferoxamine (DFO), are known as hypoxia mimics, which can elevate HIF-1α levels by blocking PHD activity even in normoxic conditions.

In this study, Desferal, deferoxamine mesylate for injection, which is approved for the treatment of acute iron intoxication and chronic iron overload, was used to explore the beneficial effects on preventing aging-induced bone loss and mitigating dysfunction of aged BMSCs. High-dose Desferal significantly prevented bone loss in aged rats. Compared with controls, the ex vivo experiments showed that short-term Desferal administration could promote the potential of BMSC growth and improve the rebalance of osteogenic and adipogenic differentiation, as well as rejuvenate senescent BMSCs and revise the expression of stemness/senescence-associated genes. The potential of BMSCs from the Desferal group at least partly revised to the level close to that of the 2-month-old group.

Klotho Links Inflammation, Salt Sensitivity, Hypertension and Mortality in Aging

Klotho is one of the few robustly demonstrated longevity-associated genes. Greater expression extends life in mice, while reduced expression shortens life. Present investigations of the mechanisms by which klotho produces effects on life span are largely focused on the direct actions of klotho in the kidney, and then the effects of kidney function on broader health. Kidney function influences cardiovascular decline and the aging of other organs through a variety of mechanisms. While klotho level is well known to correlate with the degree of cognitive decline with age, this is most likely a demonstration of the importance of kidney function and cardiovascular function on overall health. The brain suffers when its supporting organ systems suffer.

Klotho is a membrane-bound protein acting as an obligatory coreceptor for fibroblast growth factor 23 (FGF23) in the kidney and parathyroid glands. The extracellular portion of its molecule may be cleaved and released into the blood and produces multiple endocrine effects. Klotho exerts anti-inflammatory and antioxidative activities that may explain its ageing suppression effects evidenced in mice; it also modulates mineral metabolism and FGF23 activities and limits their negative impact on cardiovascular system.

Clinical studies have found that circulating Klotho is associated with myocardial hypertrophy, coronary artery disease, and stroke, and may also be involved in the pathogenesis of salt-sensitive hypertension with a mechanism sustained by inflammatory cytokines. As a consequence, patients maintaining high serum levels of Klotho not only show decreased cardiovascular mortality but also non-cardiovascular mortality.

These findings suggest that Klotho may represent a bridge between inflammation, salt sensitivity, hypertension and mortality. This may be particularly relevant in patients with chronic kidney disease who have decreased Klotho levels in tissues and blood.


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