Fight Aging! Newsletter, May 31st 2021

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  • Towards Mitochondrial Replacement Therapies
  • Senescent Cells in the Vascular System as a Cause of Declining Neurogenesis
  • How Much Funding Does the Methuselah Foundation Now Have as a Result of Vitalik Buterin's Donation?
  • A Short In Vivo Reprogramming Treatment Modestly Slows Accelerated Aging in Progeroid Mice
  • Targeting Senescent Cells to Reverse the Aging of the Kidneys
  • Towards Better Scaffolds for Muscle Regeneration
  • A Popular Science View of the State of Research into Young Blood versus Old Blood
  • Digging Deeper into the Mechanisms of Calorie Restriction in Yeast
  • A Blood Protein Signature that Correlates with Alzheimer's Risk
  • Extracellular Vesicles from Induced Pluripotent Stem Cells Treat Disk Degeneration
  • Cell Signaling via Exosomes in the Development of Vascular Calcification
  • High-Intensity Intermittent Training Improves Spatial Memory in Rats
  • Towards a Practical, Palatable Low Methionine Diet
  • Vascular Degeneration in the Brain as the Common Link Between Lifestyle and Dementia
  • Mitochondrial Dysfunction as a Cause of Atrial Fibrillation

Towards Mitochondrial Replacement Therapies

A great deal of evidence shows that declining mitochondrial function is important to the aging process. This is directly downstream of various forms of damage, such as to mitochondrial DNA. It is also a long way downstream from a range of other forms of age-related disarray that lead to epigenetic changes that impact mitochondrial function - far enough downstream that it is unclear as to how exactly the causes of aging produce this outcome. One common view is that the quality control process of mitophagy suffers as the result of reduced production of necessary proteins, and thus damaged mitochondria accumulate.

Thus we come to mitochondrial replacement as a form of therapy. Cells do take up mitochondria from the surrounding medium, and so it is possible in principle to deliver large numbers of mitochondria into the body and expect to see results. Some progress has been made in this direction; see the biotech startup Cellvie, for example. The big unanswered question for those of us interested in rejuvenation is the degree to which the effects of this therapy will last. Will fresh mitochondria quickly succumb to the same issues of the aged environment that lead to loss of native mitochondrial function? The fastest way to find out is to try.

Mitochondrial Transplantation as a Novel Therapeutic Strategy for Mitochondrial Diseases

In recent years, advances in molecular and biochemical methodologies have led to a better understanding of mitochondrial defects and their mechanisms as the cause of various diseases, but therapies for mitochondrial disorders are still insufficient. Mitochondrial transplantation is an innovative strategy for the treatment of mitochondrial dysfunction to overcome the limitations of therapies using agents. Mitochondrial transplantation aims to transfer functional exogenous mitochondria into mitochondrion-defective cells for recovery or prevention of mitochondrial diseases. Simply put, replacing an old engine with a new one to regain its function.

Recently, a considerable number of studies demonstrated the effectiveness of mitochondrial transplantation in various diseases. There are many reports of mitotherapy in tissues, animal models and even in patients, as well as in vitro. These include neurological diseases, drug-induced liver toxicity and liver disease, including fatty liver and myocardial ischemia-reperfusion injury. Several studies have evaluated the improvement in mitochondrial function via mitochondrial transfer in neurological disease models. Researchers intravenously injected mitochondria isolated from human hepatoma cells (HepG2 cells) into neurotoxin-induced Parkinson's disease (PD) mouse brain. The recipient mouse suppressed PD progression by increasing the activity of the electron transport chain (ETC), and reduced free radical generation and apoptotic cells.

To increase mitochondrial delivery efficiency, more advanced techniques have been used. One study showed the enhanced delivery and functionality of allogenic exogenous mitochondria using peptide-mediated delivery by conjugating a cell penetrating peptide, Pep-1. The result of transplanting Pep-1-labeled mitochondria into brain tissues of a PD rat model demonstrated that mitochondrial complex I protein and mitochondrial dynamics were restored in dopaminergic neurons, which also improved oxidative DNA damage. The removal of dopaminergic neuron degeneration due to a neurotoxin was also observed in the PD rat model.

Senescent Cells in the Vascular System as a Cause of Declining Neurogenesis

The accumulation of senescent cells with age occurs throughout the body. The pace at which cells become senescent increases, thanks to growing levels of damage, and the pace at which senescent cells are destroyed slows down, largely due to immune system decline. Senescent cell secrete a mix of signals that provokes chronic inflammation, disruption of tissue structure and maintenance, and, further, detrimentally alters cellular behavior in a variety of other ways. This signaling environment actively creates and maintains dysfunction in the immune system and organs. Targeted removal of senescent cells in mice, using senolytic therapies, produces rapid and sizable rejuvenation of numerous aspects of aging.

Researchers are steadily exploring the enormous number of proven and potential connections between senescent cells in specific locations in the body and specific age-related conditions or aspects of degenerative aging. In today's example, researchers propose a direct link between the senescent cells that arise in the vascular system and the age-related decline of neurogenesis in the brain. Neurogenesis is the creation of new neurons that occurs in at least some parts of the mammalian brain, followed by the integration of those cells into established neural networks. It is vital to maintenance of brain tissue, memory, and other cognitive functions, and reversing its decline with age is an important goal for the regenerative medicine community.

Vascular Senescence: A Potential Bridge Between Physiological Aging and Neurogenic Decline

The adult mammalian brain contains distinct neurogenic niches harboring populations of neural stem cells (NSCs) with the capacity to sustain the generation of specific subtypes of neurons during the lifetime. However, their ability to produce new progeny declines with age. The microenvironment of these specialized niches provides multiple cellular and molecular signals that condition NSC behavior and potential. Among the different niche components, vasculature has gained increasing interest over the years due to its undeniable role in NSC regulation and its therapeutic potential for neurogenesis enhancement.

NSCs are uniquely positioned to receive both locally secreted factors and adhesion-mediated signals derived from vascular elements. Furthermore, studies of parabiosis indicate that NSCs are also exposed to blood-borne factors, sensing and responding to the systemic circulation. Both structural and functional alterations occur in vasculature with age at the cellular level that can affect the proper extrinsic regulation of NSCs. Additionally, blood exchange experiments in heterochronic parabionts have revealed that age-associated changes in blood composition also contribute to adult neurogenesis impairment in the elderly. Although the mechanisms of vascular- or blood-derived signaling in aging are still not fully understood, a general feature of organismal aging is the accumulation of senescent cells, which act as sources of inflammatory and other detrimental signals that can negatively impact on neighboring cells.

This review focuses on the interactions between vascular senescence, circulating pro-senescence factors, and the decrease in NSC potential during aging. Understanding the mechanisms of NSC dynamics in the aging brain could lead to new therapeutic approaches, potentially including senolysis, to target age-dependent brain decline.

How Much Funding Does the Methuselah Foundation Now Have as a Result of Vitalik Buterin's Donation?

The Methuselah Foundation is one of the formative non-profits focused on achieving progress towards the foreseeable technologies of human rejuvenation. The foundation was the original home of the first SENS research programs before they were spun out into the SENS Research Foundation, and is now focused on an eclectic range of activities that prominently features support for tissue engineering, as well as the formation of an investment fund for longevity industry startups, among other programs.

Vitalik Buterin, who founded the Ethereum blockchain initiative, and has become a high net worth philanthropist as a result, recently made a sizable gift of cryptocurrency to the Methuselah Foundation. Buterin has spoken publicly in support of rejuvenation therapies as an important goal for medical development, and this is the latest and largest in his donations in this space. When I noted this last week, I only mentioned the value of the Ether (ETH) that was donated, somewhere north of 2 million at the time of reporting, and not the very much larger amount of the Dogelon currency (ELON). I also said that I was not going to explain any of the general weirdness that comes along with the cryptocurrency space and events therein. Not my circus! However, if one wants to try to answer the question of how much funding the Methuselah Foundation now has, some explanation will be necessary.

It is easy to create a new cryptocurrency. There are a lot of them. Many of these are created as a joke, an act of Dadaist art, a get rich quick scheme, an altruistic cause, or some combination of all of these. It is also usually quite easy to convert ownership cryptocurrency A into ownership in cryptocurrency B, so all of the economic activity in the big currencies has a way of spilling over into the small ones, even the jokes. To the extent that the existence of Bitcoin and Ethereum is solving someone's large set of problems (such as, cynically, how to export funds from China), there will be traffic and value in currencies like Dogelon, which appears to have been created as, in essence, an altruistic joke, with a little of Dada thrown in by choosing to burn tokens by giving them to Vitalik Buterin rather than a null entity. Buterin is only playing along in the creation of art by giving all of those tokens to charitable causes, and in doing so throwing the system into upheaval.

Dogelon is, however, thinly traded. The present market price of any thinly traded asset is essentially a fiction. Manipulators can move it more or less as they like, one should assume that they already have, and it is otherwise unconnected from the reality of what the price might be for any sizable sale. Price is heavily dependent on what people think that the major holders are likely to do. If the major holder, for example, commits to only sell a little of their holdings over time in a structured and predictable way, then it is back to business as usual. Otherwise, other holders head for the exits and the price heads to zero. That process of immolation did get underway for Dogelon immediately following Vitalik's donation, and it is thus in the interest of the Methuselah Foundation to publicly suggest that this reaction is overblown.

Which is all to say that while the present value of the Methuselah Foundation Dogelon holdings is something like 80 million, if one is to trust the market price, which one shouldn't, in practice the foundation might turn out to have close to zero in value. There is a limited ability to turn any of that fictional thinly traded alleged value into actual funds for research programs without crashing the currency. It does seem plausible that a good, measured, well communicated strategy could extract millions to fund the non-profit over the years ahead, however, and the foundation staff appear to be taking the right steps towards that goal.

Our Promise to Steward Dogelon (ELON) Value Long Term

Methuselah Foundation now controls 43% of the world's Dogelon Mars (ELON) cryptocurrency and today announced in a press release that to maximize the ELON's long-term value, the non-profit will steward the holdings for at least a year. Any future sales would be done to preserve the cryptocurrency's value while advancing the Foundation's mission.

The ELON was received through a generous donation from Vitalik Buterin, co-founder of Ethereum and a visionary computer programmer. The gift was received on May 12, 2021 and surprised the rapidly growing Dogelon Mars community. It was expected that Buterin would permanently retain his $ELON holdings. The donation raised liquidity concerns for the ELON, threatening its value and circulation.

"Because our mission to extend the healthy human lifespan requires a long-term view, Methuselah Foundation focuses on lasting achievements, not short-term rewards. We will take the same nurturing approach with our Dogelon Mars holdings because we understand that the cryptocurrency's value depends on maintaining the public's confidence and capturing its imagination, much like baseball cards or other collectibles. We want the ELON to keep accruing value over the long term."

A Short In Vivo Reprogramming Treatment Modestly Slows Accelerated Aging in Progeroid Mice

Progeria, caused by loss of function mutations in the lamin A gene, is not accelerated aging. It is an example to demonstrate that many forms of cellular damage and disarray, when present to a greatly exaggerated degree, can in some ways mimic manifestations of aging. Aging is, after all, a process of cellular damage and disarray. It is, however, a specific balance of various forms of damage. Change that balance radically, or employ other forms of damage, as is the case in progeroid mice, and the outcome can no longer be called aging. It becomes a challenge to determine whether interventions that help ameliorate the harms of progeria would help meaningfully with normal aging; that depends strongly on the details of each case.

There is a growing interest in applying cellular reprogramming as an in vivo treatment. The goal is to deliver enough of the reprogramming factors to make a significant number of cells become more functional, by improving mitochondrial function and reversing a range of age-related epigenetic changes, but without forcing cells to abandon their roles to become induced pluripotent stem cells. A small number of such conversations is probably acceptable, given the outcome of stem cell therapies, but at some point too much of that will produce cancer or outright tissue failure. Thus initial explorations of reprogramming as a therapy are focused on short or otherwise limited exposure to the reprogramming agents.

A single short reprogramming early in life improves fitness and increases lifespan in old age

In 2006, it was shown that mouse somatic cells can be converted into pluripotent cells (iPSCs) by inducing the expression of four transcription factors: OCT4, SOX2, KLF4, and c-MYC (OSKM). This process of cellular reprogramming induces a global remodeling of epigenetic landscape to revert cell identity to a pluripotent embryonic-like state. Exploiting cell reprogramming offers an alternative route for cell therapy to restore organ and tissue function. Somatic cells can be reprogrammed into iPSCs, then modified or corrected in vitro before being re-differentiated into cells, tissues or organs for replacement in the donor or an immune-compatible patient.

Previous experiments using a reprogrammable mouse model demonstrated that a cyclic induction of OSKM two days a week, over the entire extremely short lifetime of a homozygous accelerated aging mouse model, increased longevity, through a potential chronically unstable state of epigenetic remodeling. These mice have a mutated Lmna gene that produces high level of the natural aging protein progerin.

In this study, we investigate a single short period of in vivo OSKM induction as pre-clinical proof of principle for a potential usage in clinic to prevent aging defects. We focused on heterozygous animals, which have moderate lifespan and levels of progerin, as these heterozygotes might be extremely sensitive to anti-aging therapies. As a short OSKM induction, was described to ameliorate immediate tissue regeneration after experimentally induced tissues injuries, we wondered whether a short period of OSKM genes induction might improve lifespan and tissues aging of heterozygotes mice.

Surprisingly, we found that many health measures, and longevity itself, were ameliorated in elderly mice, by a single two and a half weeks treatment earlier in life, at two months of age. This outcome was associated with a differential DNA methylation signature, suggesting that a "memorized effect" initiated by our short induction protocol early in life might be involved in a more juvenile physiology.

Targeting Senescent Cells to Reverse the Aging of the Kidneys

Senescent cells accumulate with age and cause a wide range of pathologies. They contribute in some way to near all of the common, ultimately fatal age-related conditions. Senescent cells secrete a mix of signals that produces chronic inflammation, disrupts tissue maintenance to encourage fibrosis, and changes the behavior of other cells for the worse in numerous ways. It is the signaling that allows the comparatively small fraction of senescent cells in any given aged tissue to cause such widespread harm.

Destroying senescent cells in a targeted fashion via the use of senolytic therapies has shown great promise in animal studies, and early human trials have show that at least some of those therapies can also destroy senescent cells in human patients. While scores of age-related conditions have been reversed in mice, and life span extended, via the use of senolytics, the clinical research community is initially focused on establishing efficacy for only a few conditions in human trials.

One of those conditions is chronic kidney disease, characterized by fibrosis, inflammation, and other effects likely caused in large part by senescent cells. Today's open access paper is a discussion of the science underlying this portion of the field.

Targeting Premature Renal Aging: from Molecular Mechanisms of Cellular Senescence to Senolytic Trials

Kidneys from elderly are associated with structural changes as the loss in renal mass, glomerulosclerosis, glomerular basement membrane thickening, tubular atrophy, interstitial fibrosis, and the arteriosclerosis. Furthermore, aged kidneys are characterized by functional impairments as reduced glomerular filtration rate (GFR), decrease in urine concentration, plasma flow, and sodium resorption. In healthy aging conditions, despite the gradual but constant drop in GFR (5-10% per decade after the age of 35 years), renal function can be preserved by compensatory mechanisms as hypertrophy of unaffected nephrons or by vasodilatory prostaglandins that can moderate excessive vasoconstriction.

However, beyond their functional reserve capacity, aged kidneys exhibit an increased susceptibility to "a second hit" damage as during acute kidney injury (AKI) occurrence, such as after a nephrotoxic drugs treatment (i.e., contrast agents) or during a bacterial induced systemic inflammatory response (i.e., sepsis or other infections). In the last few years, it has become extremely clear that maladaptive repair after an AKI episode can predispose to chronic kidney disease (CKD), and ultimately, depending on genetic, immunological, and environmental factors, to end-stage renal disease (ESRD).

The central mechanism underlying renal physiological and pathological aging is characterized by cellular senescence. Cellular senescence refers to a complex program that can be initiated by various cellular stresses and is characterized by cycle arrest despite the presence of growth stimuli. In renal aging-related diseases, senescent cells chronically accumulate in renal parenchyma, leading to tissue deterioration and to an aberrant signaling activation to different types of populations.

In the last few years, the development of compounds able to directly eliminate senescent cells or to target the effects of senescent cells has found a vivid interest in the complex field of age-related pathologies. Senotherapeutic agents hold promise for the utilization in treating disorders related to senescent cell accumulation such as neurodegenerative diseases, atherosclerosis, cancers, kidney injury, chronic obstructive lung disease, idiopathic pulmonary fibrosis, diabetes, as well as complications of organ transplantation, radiation, and chemotherapy. The term "senotherapeutic drugs" includes different molecules as the senolytics (compounds that kill senescent cells selectively), senomorphics (i.e., molecules that can inhibit SASP, modulate functions and morphology of senescence cells, or delay the progression of young cells to senescent cells), and senoinflammatory mediators (that are immune-system effectors of the clearance of senescent cells).

Senescent cell viability is strictly dependent on apoptosis resistance and anti-apoptotic signaling thus leading researchers in nephrology to extend the application of senotherapeutic strategies adopted in oncology also to prevent the complications of kidney aging.

Towards Better Scaffolds for Muscle Regeneration

Building better scaffolding materials for tissue regrowth is one important line of work in the regenerative medicine. The idea is to better mimic necessary characteristics of the natural extracellular matrix, to make the cells inhabiting the scaffold material behave in ways that are conducive to regrowth and regeneration. The open access paper noted here is an example of this sort of ongoing research and development, tackling one small aspect of scaffold materials for one tissue type.

To achieve rapid skeletal muscle function restoration, many attempts have been made to bioengineer functional muscle constructs by employing physical, biochemical, or biological cues. Here, we develop a self-aligned skeletal muscle construct by printing a photo-crosslinkable skeletal muscle extracellular matrix-derived bioink together with poly(vinyl alcohol) that contains human muscle progenitor cells.

To induce the self-alignment of human muscle progenitor cells, in situ uniaxially aligned micro-topographical structure in the printed constructs is created by a fibrillation/leaching of poly(vinyl alcohol) after the printing process. The in vitro results demonstrate that the synergistic effect of tissue-specific biochemical signals, obtained from the skeletal muscle extracellular matrix-derived bioink, and topographical cues, obtained from the poly(vinyl alcohol) fibrillation, improves the myogenic differentiation of the printed human muscle progenitor cells with cellular alignment. Moreover, this self-aligned muscle construct shows the accelerated integration with neural networks and vascular ingrowth in vivo, resulting in rapid restoration of muscle function.

Thus we demonstrate that combined biochemical and topographic cues on the 3D bioprinted skeletal muscle constructs can effectively reconstruct the extensive muscle defect injuries.

A Popular Science View of the State of Research into Young Blood versus Old Blood

Research spawned by heterochronic parabiosis studies, in which an old and a young animal have their circulatory systems linked, continues to provide surprises. There is considerable debate over whether helpful factors in young blood versus a dilution of harmful factors in old blood provide the majority of the benefits to the older animal, with the evidence favoring the latter at the present time. Dilution of blood plasma has been shown to produce benefits in animal studies, but that involves adding albumin to avoid diluting that essential protein. Researchers recently showed that adding recombinant albumin, and skipping the dilution, still produces benefits to health in animal studies. This may change the understanding of what is going on here yet again.

Last year, two self-described "biohackers" in Russia had themselves hooked up to blood collection machines that replaced approximately half of the plasma coursing through their veins with salty water. Three days later, the men tested their blood for hormones, fats and other indicators of general well-being. The procedure, it seemed, had improved various aspects of immunity, liver function and cholesterol metabolism.

Irina and Michael Conboy initially tried taking the reductionist drug development approach. They identified two biochemical pathways implicated with aging, pharmacologically recalibrated both in old mice, and found that the animals' brains, livers and muscles showed signs of rejuvenation. But a more rudimentary intervention they tried did better still. In a series of experiments that inspired the Russian biohackers, the Conboys simply replaced half of the animals' plasma with saline. (They, like the biohackers, also added back albumin, a protein essential for maintaining the proper fluid balance in the blood.) The dilution of pro-aging factors proved sufficient to activate a series of molecular changes in the mice that unleashed age-defying factors, leading to cognitive improvements and reduced inflammation in the brain.

Although other researchers saw many of the same effects when they administered young blood to mice, Irina Conboy suspects that those benefits had more to do with the dilution of old plasma than any enrichments provided by the young plasma. On balance, her research suggests that the detrimental effects of circulatory proteins in old blood - which include the suppression of youthful factors - are far stronger than any rejuvenating qualities of molecules added via young blood.

Many age-elevated factors have been identified, but finding drugs for each one is a challenge. Plasma dilution, by comparison, knocks them all down - and others as yet unknown - in one fell swoop. The Conboys founded a company to develop the plasma exchange strategy further. Others feel similarly dubious about young blood as a therapeutic. "This approach reminds me of trying to refresh sour milk by pouring fresh milk into it," says Iryna Pishel, who previously tested the anti-aging effects of young plasma on old mice and saw little impact on lifespan or immunological markers of aging.

Digging Deeper into the Mechanisms of Calorie Restriction in Yeast

Calorie restriction promotes longevity, slowing the progression aging via sweeping metabolic changes across an entire organism. The metabolic changes it produces in cells are very similar in all species studied to date. This is one of the reasons why calorie restriction is so well studied: one can carry out low-cost experiments in yeast and nonetheless learn something that is likely relevant to human biochemistry. Still, it is well established that calorie restriction is much better at extending life in short-lived species. In humans there are clear improvements to long-term health, but nowhere near the same degree of life extension observed in calorie restricted mice.

Caloric restriction and the tor1Δ mutation are robust geroprotectors in yeast and other eukaryotes. Lithocholic acid is a potent geroprotector in Saccharomyces cerevisiae. Here, we used liquid chromatography coupled with tandem mass spectrometry method of non-targeted metabolomics to compare the effects of these three geroprotectors on the intracellular metabolome of chronologically aging budding yeast. Yeast cells were cultured in a nutrient-rich medium. Our metabolomic analysis identified and quantitated 193 structurally and functionally diverse water-soluble metabolites implicated in the major pathways of cellular metabolism.

We show that the three different geroprotectors create distinct metabolic profiles throughout the entire chronological lifespan of S. cerevisiae. We demonstrate that caloric restriction generates a unique metabolic pattern. Unlike the tor1Δ mutation or lithocholic acid, it slows down the metabolic pathway for sulfur amino acid biosynthesis from aspartate, sulfate, and 5-methyltetrahydrofolate. Consequently, caloric restriction significantly lowers the intracellular concentrations of methionine, S-adenosylmethionine, and cysteine. We also noticed that the low-calorie diet, but not the tor1Δ mutation or lithocholic acid, decreases intracellular ATP, increases the ADP:ATP and AMP:ATP ratios, and rises intracellular ADP during chronological aging.

These findings suggest a hypothetical model of how the observed CR-specific remodeling of cellular metabolism delays the chronological aging of yeast. The key aspects of this model are as follows: 1) a life-long decline in the intracellular concentrations of cysteine and methionine weakens tRNA thiolation, thus slowing down the pro-aging process of protein synthesis, 2) a decrease of intracellular methionine throughout the chronological lifespan attenuates a direct methionine-driven stimulation of the pro-aging Tor1 pathway, thereby lowering the inhibitory effect of Tor1 on autophagy and other anti-aging processes, 3) a deterioration in intracellular methionine concentration at diverse stages of chronological aging also weakens a methionine-dependent suppression of the proteasomal degradation of damaged and dysfunctional proteins, a known anti-aging process, 4) a decline in S-adenosylmethionine concentration throughout the chronological lifespan lowers the ability of the protein phosphatase Ppa2p to stimulate the pro-aging Tor1 pathway, and 5) a rise in the ADP:ATP and AMP:ATP ratios on most days of yeast chronological lifespan indirectly (i.e., independent of AMP or ATP binding to Snf1) stimulates the anti-aging protein kinase complex Snf1; Snf1 can also be activated directly, via an ADP binding-dependent protection of Snf1 from inactivating dephosphorylation.

A Blood Protein Signature that Correlates with Alzheimer's Risk

Signatures built from the vast array of proteins found in the blood stream, including those encapsulated in extracellular vesicles, should in principle correlate with many health conditions. This includes those conditions, such as Alzheimer's disease, characterized by a long, slow preclinical stage in which damage and metabolic disarray builds up over time. Modern machine learning techniques allow the cost-effective construction of such signatures, given a large enough database work with, and as illustrated here.

Efforts to gauge people's Alzheimer's risk before dementia arises have focused mainly on the two most obvious features of Alzheimer's brain pathology: clumps of amyloid beta protein known as plaques, and tangles of tau protein. Scientists have shown that brain imaging of plaques, and blood or cerebrospinal fluid levels of amyloid beta or tau, have some value in predicting Alzheimer's years in advance. But humans have tens of thousands of other distinct proteins in their cells and blood, and techniques for measuring many of these from a single, small blood sample have advanced in recent years. Would a more comprehensive analysis using such techniques reveal other harbingers of Alzheimer's?

An initial analysis covered blood samples taken during 2011-13 from more than 4,800 late-middle-aged participants in the Atherosclerosis Risk in Communities (ARIC) study, a large epidemiological study of heart disease-related risk factors and outcomes, recording levels of nearly 5,000 distinct proteins in the banked ARIC samples. The researchers analyzed the results and found 38 proteins whose abnormal levels were significantly associated with a higher risk of developing Alzheimer's in the five years following the blood draw.

Researchers then measured protein levels from more than 11,000 blood samples taken from much younger ARIC participants in 1993-95. They found that abnormal levels of 16 of the 38 previously identified proteins were associated with the development of Alzheimer's in the nearly two decades between that blood draw and a follow-up clinical evaluation in 2011-13.

In a further statistical analysis, the researchers compared the identified proteins with data from past studies of genetic links to Alzheimer's. The comparison suggested strongly that one of the identified proteins, SVEP1, is not just an incidental marker of Alzheimer's risk but is involved in triggering or driving the disease. SVEP1 is a protein whose normal functions remain somewhat mysterious, although in a study published earlier this year it was linked to the thickened artery condition, atherosclerosis, which underlies heart attacks and strokes. Other proteins associated with Alzheimer's risk in the new study included several key immune proteins - which is consistent with decades of findings linking Alzheimer's to abnormally intense immune activity in the brain.

Extracellular Vesicles from Induced Pluripotent Stem Cells Treat Disk Degeneration

Harvesting extracellular vesicles from cell cultures and then delivering them to patients is a way to obtain the benefits of first generation stem cell therapies with considerably fewer issues that delivery of cells. One doesn't have to worry about compatibility with the patient, for example. Logistically, vesicles are much easier to store, transport, and employ in therapy than cells. Since most of these first generation stem cell therapies achieve near all of their benefits via cell signaling in the short period before the transplanted cells die, the use of vesicles is a practical alternative, and an area in which considerable effort is going towards clinical development and application. Alongside the usual mix of companies working on therapies and researchers running animal studies, such as the one noted here, it is also quite possible for anyone in the US today to arrange extracellular vesicle injections given a little research into providers and a cooperative physician.

Recently, mesenchymal stem cell (MSC) transplantation has shown promising therapeutic potential in alleviating ageing-associated phenotypes. Despite their potential therapeutic applications, the direct use of stem cell transplantation still faces several hurdles, such as the risk of tumorigenesis and undesirable immune responses. Recent evidence has indicated the therapeutic potential of small extracellular vesicles (sEVs) secreted by MSCs derived from different tissues in alleviating cellular senescence, while avoiding the undesirable immune response and the risk of tumorigenesis. However, harvesting MSCs from different tissues, such as the bone marrow and adipose tissue, is invasive. In addition, limitations such as the decreased proliferative potential and therapeutic efficacy of MSCs during in vitro expansion have impeded the industrial production of sEVs.

Induced pluripotent stem cells (iPSCs) are a subpopulation of stem cells that can be reprogrammed from any tissue type in the body. iPSCs have a unique ability to proliferate indefinitely and display totipotency in vitro. Furthermore, induced pluripotent stem cell-derived MSCs (iMSCs) possess MSC-like therapeutic effects in tissue regeneration treatments. Along with the advantages of the acquisition and proliferation of iMSCs, compared with those of MSCs, sEVs can be abundantly obtained from iMSCs, which is convenient for industrial production.

Intervertebral disc degeneration (IVDD) models were established by puncturing discs from the tails of rats. Then, iMSC-sEVs were injected into the punctured discs. The degeneration of punctured discs was assessed. The age-related phenotypes were used to determine the effects of iMSC-sEVs on senescent nucleus pulposus cells (NPCs) in vitro. Western blotting was used to detect the expression of Sirt6. miRNA sequencing analysis was used to find miRNAs that potentially mediate the activation of Sirt6.

After injecting iMSC-sEVs, NPC senescence and IVDD were significantly improved. iMSC-sEVs could rejuvenate senescent NPCs and restore the age-related function by activating the Sirt6 pathway in vitro. Further, microRNA sequence analysis showed that iMSC-sEVs were highly enriched in miR-105-5p, which played a pivotal role in the iMSC-sEV-mediated therapeutic effect by downregulating the level of the cAMP-specific hydrolase PDE4D and could lead to Sirt6 activation. In conclusion, iMSC-sEVs could rejuvenate the senescence of NPCs and attenuate the development of IVDD.

Cell Signaling via Exosomes in the Development of Vascular Calcification

Vascular calcification is a feature of aging, a process in which cells in the blood vessel wall take on inappropriate identities and activities that are more appropriate to bone tissue. Evidence of recent years implicates chronic inflammation and the presence of senescent cells in this process. Senescent cells cause harm via their signaling, a good fraction of which is carried via forms of extracellular vesicle, such as exosomes. Here, researchers review what is known of the signaling that may be involved in changing the behavior of cells towards calcification processes. Whether or not it is necessary to understand all of this in order to find a way to block calcification is an interesting question: how much benefit will be produced by reducing inflammation and clearing senescent cells? If a sizable fraction of the problem remains, then a greater understanding will likely be required for further progress.

Vascular calcification (VC) is the abnormal deposition of calcium, phosphorus, and other minerals in the vessel wall in the form of hydroxyapatite. Over 60% of elderly people have calcium salt deposits in the vascular walls, and VC is closely associated with mortality from cardiovascular diseases in the aged population. Traditionally, calcification is considered as a degenerative disease associated with the aging process. However, increasing evidence has demonstrated that the occurrence and development of calcification is an active and highly regulated complex biological process, which is regulated by multiple factors, such as phenotypic conversion of vascular smooth muscle cells (VSMCs), metabolic homeostasis of calcium and phosphate, inflammation, oxidative stress, autophagy, and extracellular vesicle (EVs) release, among others.

Exosomes, as important intercellular message transporters, have recently been shown to participate in VC. Exosomes cargos include RNA, cytokines, proteins, and lipids. Studies have shown that the components of exosomes cargos differ significantly according to the cells that the exosomes origin. A large number of studies have focused on the role of exosomes in inducing mineral deposition during VC, but the role of exosomes in information transfer in VC has not yet been clarified.

Exosomes from different sources can participate in the regulation of VC by transporting miRNAs to recipient VSMCs. Exosomes released by mineralized osteoblasts contribute to the osteogenic differentiation of cells via a complex network of exosomal miRNAs. Bone marrow mesenchymal stem cell (MSC)-derived exosomes can alleviate high phosphorus-induced calcification in human aortic VSMCs through the modification of miRNA profiles. Exosomes derived from VSMCs are rich in miRNA-143 and proteins regulating cell adhesion and migration, which can participate in the regulation of cell proliferation and migration through autocrine and paracrine manners. An in vivo study showed that exosomes derived from melatonin-treated VSMCs could reduce VC in mice, while these effects were largely abolished by inhibition of exosomal miR-204 or miR-211.

The underlying mechanisms by which exosomes affect VC via transporting miRNA are still not fully understood and may vary among different conditions. Changes of miRNAs in exosomes can regulate osteogenic differentiation of cells by promoting the expression of Runx2 and activating related signaling pathways, for example, the Wnt/β-catenin pathways. Studies have shown that miRNAs with increased expression in the VC process can promote the osteogenic transformation of smooth muscle cells by targeting anti-calcification proteins or contractility markers, while miRNAs with decreased expression can inhibit the osteogenic transformation of SMCs by targeting osteogenic transcription factors. Further research on the characteristics of exosomes and their role in VC is needed and expected to provide novel ideas and targets for the clinical diagnosis and treatment of VC.

High-Intensity Intermittent Training Improves Spatial Memory in Rats

There is plenty of evidence to show that exercise improves memory, both very quickly and for a short time following any specific bout of exercise, and over the long term due to regular exercise. The mechanisms involved here are varied, likely a combination of cerebral blood flow changes and signaling molecules such as BDNF that are involved in the regulation of neurogenesis. Neurogenesis, the creation and integration of new neurons into the brain, is vital to memory function.

Researchers found that, despite only covering about one-third of the distance in high-intensity intermittent training (HIIT) compared with that covered in endurance training, similar improvements in exercise capacity and brain function were observed for both forms of exercise. In the experiment, rats were assigned to 1 of 3 groups - resting, endurance running, or alternating intervals (short sprints and rest) - during training sessions on treadmills 5 days/week for 4 weeks.

Both endurance running and HIIT resulted in weight loss, greater muscle mass, and the ability to exercise longer compared with controls; however, increased cellular aerobic capacity was found in the soleus (a muscle with predominantly slow-twitch fibers that makes it functionally well suited to endurance) and in the plantaris (a muscle with predominantly fast-twitch fibers for meeting high-energy functional demands) in the endurance-running and HIIT groups, respectively.

Rats in both groups demonstrated having better memory of spatial learning trials in searching for an escape platform in a water maze. In the hippocampus, increased cell development, neurogenesis, was also observed for both forms of exercise; however, levels of a signaling protein that promotes neurogenesis (BDNF) were increased by HIIT but not by endurance running, whereas the levels of its receptor (TrkB) were increased by both. Given that BDNF expression is known to be affected by exercise, why didn't endurance running increase BDNF expression? The answer may lie in the mediating role of stress on BDNF expression; exercise is a type of stress. While stress indicators in both exercise groups were found to be similar, this line of enquiry may lead to future studies:

Towards a Practical, Palatable Low Methionine Diet

Low methionine intake has been shown, in animal studies, to mimic many of the same effects of calorie restriction, which is to say improved health and extended life span. A sizable fraction of the trigger mechanisms that produce improved metabolism as a result of lowered calorie intake appear to depend on methionine levels. Attempting a reduced methionine diet is about the hardest thing that any casual health enthusiast could choose to undertake when it comes to dietary self-experimentation. The sources of data on methionine content are incomplete and contradictory, and just about every common food stable is packed full of methionine. The specially formulated medical diets for people with conditions that require very low methionine intake in order to avoid pathology are expensive and unpleasant to consume in comparison to normal food. But perhaps there is a better way forward, and, given time, we may start to see low methionine options becoming more affordable and palatable.

"We've known for years that restricting the amino acid methionine in the diet produces immediate and lasting improvements in nearly every biomarker of metabolic health. The problem is that methionine-restricted diets have been difficult to implement because they taste so bad." Until now. Restricting methionine normally involves diets formulated with elemental (e.g., individual) amino acids. Individual amino acids are the building blocks of proteins. But diets made from elemental amino acids taste bad, and few are willing to tolerate the regimen.

A palatable solution emerged from the development of methods to selectively delete methionine from casein, the main protein in milk and cheese. Researches conducted proof-of-concept testing to establish that oxidized casein could be used to implement methionine restriction without the objectionable taste of the standard elemental diet. More than two-thirds of Americans are overweight or have obesity. More than 40 percent of adults have prediabetes or type 2 diabetes. A diet that offsets all the major components of metabolic disease would have an enormous impact.

A palatable, methionine-restricted diet could also ease a major frustration for those struggling to manage their weight. Each year, millions of people improve their metabolism and lose weight by reducing how much they eat. But eventually, most people gain back those pounds.

Vascular Degeneration in the Brain as the Common Link Between Lifestyle and Dementia

Researchers here propose that the unifying underlying mechanism for lifestyle influences on dementia risk is chronic inflammation. That inflammation causes vascular degeneration and a consequent decline in the blood supply to the brain, which in turn contributes - to some degree - to all of the observed issues in the aging brain. When present to a large degree, these vascular issues are categorized as vascular dementia, a widely studied condition. But it is entirely plausible that subclinical vascular degeneration is an important mediating factor linking lifestyle and dementia. A competing hypothesis involves the role of persistent infection, and correlation between lifestyle factors and risk of suffering such infections. This also would be expected to proceed via raised levels of inflammation in the brain. The state of the immune system is indeed an important factor in aging.

The 2020 report of the Lancet Commission identified twelve potentially modifiable risk factors for dementia including less education, hypertension, hearing impairment, smoking, obesity, depression, physical inactivity, diabetes, and low social contact, and suggested that 40% of worldwide dementias may be due to these factors. Research has also provided two additional important observations relevant to the etiology of dementia. The first was that drugs that successfully eliminated cerebral accumulations of beta amyloid have so far shown only modest impact on cognitive deficits, although trials are still ongoing. Ever since the original description that these proteins were present in the brains of individuals dying with dementia, they were considered to be etiologically significant in inducing dementia, and the modest impact they have had to date has forced a reappraisal of our approach to dementia.

The second landmark observation was that a decline in cerebral blood flow (CBF) was an early cerebral event that heralded the decline in cognitive function and may precede the appearance of the clinical syndrome by many years. This finding confirmed that vascular insufficiency is a major etiologic factor that anticipates the onset of cognitive deficits, and that the protein deposits found in the brain of demented individuals were more likely a consequence of the disease rather than its cause. While this was a major step forward in our understanding of the etiology of dementia, it left open the question: do all harmful lifestyles lead to cerebral hypoperfusion? If so, what are the physiological mechanisms that lead to the decline in CBF when a harmful lifestyle has persisted?

Several publications have proposed that inflammation may be the link between lifestyle, genetics, and Alzheimer's disease, but the mechanisms that link inflammation to this outcome are not clear. This review will focus on three lifestyle factors that negatively impact cognition, namely obesity, sedentary behavior, and insufficient sleep. In each case, a summary of the research associating the lifestyle to subsequent cognitive decline will be presented, and the impact of the lifestyle on cerebral vascular perfusion will be explored. The potential mechanisms linking the lifestyle to its eventual impact on perfusion will then be reviewed. A unifying hypothesis will be proposed, namely, that all lifestyles that negatively impact cognition do so through the activation of inflammatory factors, which then lead to small vessel disease, resulting in a reduction in cerebral perfusion and causing atrophy of structures essential for normal cognition.

Mitochondrial Dysfunction as a Cause of Atrial Fibrillation

For any given age-related condition, you will find papers in the literature that focus on one mechanism of aging and its contribution to that condition. Usually these are reviews covering the details of the mechanism and how it causes pathology, or the epidemiology of the mechanism in the field, as absent an effective means of intervention it is very challenging to establish just how large a contribution that mechanism actually has.

While looking through the work here on age-related mitochondrial dysfunction and atrial fibrillation, it is worth also taking a look at past work on senescent cell burden as a cause of atrial fibrillation, potentially via inflammatory, pro-growth signaling that leads to fibrosis in heart tissue. In both cases there are approaches to addressing the issue, mitochondrial replacement and senolytic drugs to destroy senescent cells, but those assessments have yet to be carried out rigorously. Until they have one, there is no way to predict which of these contributing causes is more or less important than the other.

Atrial fibrillation (AF) is the most common cardiac arrhythmia and contributes to a high prevalence of mortality and morbidity. The shortening of telomere length has been found to be common with age. Research efforts have argued that leukocyte telomere length (LTL) shortening is related to a variety of cardiovascular diseases, including atherosclerosis, left ventricular hypertrophy, and heart failure, but the relevance to AF is still controversial. In the Cardiovascular Health Study, researchers found no relationship between mean telomere length and AF in human atrial tissue.

The mechanisms of AF remain incompletely understood. Mitochondria play an important role in oxidative stress, calcium homeostasis, and energy metabolism. Studies have shown that mitochondrial dysfunction can cause insufficient ATP production and excessive reactive oxygen species (ROS), which damages the homeostasis of Ca2+ in myocardial cells and the excitability of membranes, in turn leading to AF.

Accumulating evidence has argued that PGC-1α is a key molecule of mitochondrial function because it participates in the regulation of mitochondrial biogenesis and energy metabolism and is closely related to oxidative stress and inflammation. It plays an important role in the occurrence and development of atherosclerosis, coronary heart disease, heart failure, and other cardiovascular diseases. Some researchers have put forward the concept of a "telomere-p53-PGC axis": that is, that the shortening of telomere will activate p53 expression, thereby inhibiting PGC-1 and causing mitochondrial dysfunction.

We measured the LTL, telomere-associated molecules, and mitochondrial membrane potential (MMP) of leukocytes to ascertain if they are correlated with aging-related AF and if they could be used as novel biomarkers for it. We found that LTL and serum PGC-1α are inversely correlated with the occurrence of aging-related AF and that the MMP of AF patients was significantly decreased, indicating that mitochondrial dysfunction plays a role.

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