Fight Aging!

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Contents

• Telomerase and Follistatin Gene Therapies Delivered via Cytomegalovirus Extend Life in Mice
• Macrophage Dysfunction is the Important Target if Seeking to Treat Atherosclerosis
• Cellular Senescence in the Context of Aging, Metabolism, and Epigenetics
• Using Supercentenarian Data to Estimate Future Increases in Maximum Human Life Span
• Disruption of Elastin in the Aging Skin, and the Little that Can Presently Be Done About It
• The Redox-Senescence Axis in Aging
• Overactive Monocytes and Macrophages Contribute to the Onset of Alzheimer's Disease
• Combined Duration and Degree of Hypertension a Better Correlation with Cardiovascular Risk
• Indoles Produced by the Gut Microbiome Increase Neurogenesis
• Tryptophan and Age-Related Changes in the Gut Microbiome
• Applying Chimeric Receptor Antigens to Natural Killer Cells to Target Solid Cancers
• Epigenetic Rejuvenation During Embryogenesis
• Cellular Processes Involved in Brain Aging
• Glucose Metabolism Becomes Insufficient to Meet the Energy Demands of the Aging Hippocampus
• Delivery of α-klotho as a Basis for Neuroprotective Treatments

Telomerase and Follistatin Gene Therapies Delivered via Cytomegalovirus Extend Life in Mice
https://www.fightaging.org/archives/2021/07/telomerase-and-follistatin-gene-therapies-delivered-via-cytomegalovirus-extend-life-in-mice/

Upregulation of telomerase expression and, separately, follistatin expression have been shown to extend life in mice. In recent news, researchers report a novel approach to delivering these two genes via gene therapy, making use of cytomegalovirus (CMV) as a vector. CMV is actually a major threat to human health, and might be responsible for a great deal of the age-related decline of the immune system. Near everyone is infected by the time old age rolls around. Nonetheless, one can develop viral vectors in which replication (and thus any threat of infection) is disabled, and these are widely used as tools in research and development.

Cytomegalovirus is most analogous to adeno-associated virus (AAV) in terms of how it works to make a cell produce desired proteins without introducing new DNA into the genome. It appears to be good at delivering its cargo to immune cells in particular, which may go some way towards explaining positive outcomes for telomerase in the study noted below. Immune system function is very important in aging, and immune cells replicate dramatically in response to infection. An increased capacity to replicate may do more good in the immune system than anywhere else in the body.

Telomerase upregulation extends life via a general boost to cell function, and probably stem cell function in particular. Telomerase acts to extend telomeres, which shorten with each cell division, enabling cells to push back the Hayflick limit in order to replicate and work for longer. In mice at least, the risk of cancer due to damaged cells remaining active appears more than compensated for by improved function in the immune system or other anti-cancer mechanisms. Cancer is reduced, but exactly why this is the case is still poorly explored. It is also possible that telomerase has meaningful effects on mitochondrial health in old age via its less well explored functions in the cell. No protein has just one task in the body; evolution likes reuse.

Follistatin is an inhibitor of myostatin, which in turn suppresses muscle growth. The effect of follistatin upregulation is thus a sizable growth in muscle mass, though it also reduces inflammation, fat tissue mass, and infiltration of fat into muscle tissue, among other beneficial shifts in metabolism. Mice engineered to overexpress follistatin or lacking myostatin are very heavily muscled, and as shown in the research here, live longer than their unmodified peers.

New intranasal and injectable gene therapy for healthy life extension

How to achieve healthy longevity has remained a challenging subject in biomedical science. It has been well established that aging is associated with a reduction in telomere repeat elements at the ends of chromosomes, which in part results from insufficient telomerase activity. Importantly, the biological functions of the telomerase complex rely on telomerase reverse transcriptase (TERT). TERT plays a major role in telomerase activation, and telomerase lengthens the telomere DNA. Because telomerase supports cell proliferation and division by reducing the erosion of chromosomal ends in mitotic cells, animals deficient in TERT have shorter telomeres and shorter life spans. Recent studies on animal models have shown the therapeutic efficacy of TERT in increasing healthy longevity and reversing the aging process.

The follistatin (FST) gene encodes a monomeric secretory protein that is expressed in nearly all mammalian tissues. In muscle cells, FST functions as a negative regulator of myostatin, a myogenesis inhibitory signal protein. FST overexpression is known to increase skeletal muscle mass in transgenic mice by 194% to 327% by neutralizing the effects of various TGF-β ligands involved in muscle fiber break-down, including myostatin and activin inhibition complex. These findings strongly implicate the therapeutic potential of FST in the treatment of muscular dystrophy and muscle loss caused by aging or microgravity. Thus, TERT and FST are among prime candidates for gene therapy aimed to improve healthy life spans.

As more longevity-supporting factors are discovered, it is of interest to determine potential large capacity vectors for delivering multiple genes simultaneously. Unlike AAV, lentiviruses, or other viral vectors used for gene delivery, cytomegaloviruses have a large genome size and unique ability to incorporate multiple genes. Cytomegaloviruses also do not integrate their DNA into the host genome during the infection cycle, thus mitigating the risk of insertional mutagenesis. They also do not elicit symptomatic immune reactions in most healthy hosts. Notably, the CMV vector does not invoke genome instability and has not been identified to cause malignancies. Human CMV (HCMV) has been proven a safe delivery vector for expressing therapeutic proteins in human clinical trials.

Using mouse cytomegalovirus (MCMV) as a viral vector, we examined the therapeutic potential of TERT and FST gene therapy to offset biological aging in a mouse model. We found that the mouse cytomegalovirus (MCMV) carrying exogenous TERT or FST extended median lifespan by 41.4% and 32.5%, respectively. This is the first report of CMV being used successfully as both an intranasal and injectable gene therapy system to extend longevity. Treatment significantly improved glucose tolerance, physical performance, and prevented loss of body mass and alopecia. Telomere shortening seen with aging was ameliorated by TERT, and mitochondrial structure deterioration was halted in both treatments. Intranasal and injectable preparations performed equally well in safely and efficiently delivering gene therapy to multiple organs, with long-lasting benefits and without carcinogenicity or unwanted side effects. Translating this research to humans could have significant benefits associated with increased health span.

Macrophage Dysfunction is the Important Target if Seeking to Treat Atherosclerosis
https://www.fightaging.org/archives/2021/07/macrophage-dysfunction-is-the-important-target-if-seeking-to-treat-atherosclerosis/

Atherosclerosis is characterized by the formation of fatty plaques in blood vessel walls, narrowing and weakening vessels. It leads to heart failure, as well as heart attack and stroke as the result of rupture of a blood vessel or plaque. Near all treatments for atherosclerosis are preventative, which is the better approach to medicine, and are focused on the outcome of lowering LDL cholesterol in the bloodstream, which is, unfortunately, not the better approach to atherosclerosis.

Atherosclerosis is, at root, a condition caused by macrophage dysfunction. Macrophages are the innate immune cells tasked with clearing debris from blood vessel walls. That debris includes errant cholesterol. Cholesterol is needed everywhere in the body, but is expensive to produce, and is only made in a few places, primarily the liver. Cells do not break down excess cholesterol, but rather traffic it around the body as needed via the bloodstream. Cholesterol made in the liver is attached to LDL particles and sent out into the body. Macrophages serve a vital function in returning excess cholesterol from blood vessel walls to the bloodstream, attaching it to HDL particles which return to the liver.

This complicated system works just fine in youth, but macrophages become dysfunctional with age, faltering in their task of cholesterol uptake and hand-off to HDL particles. This is thought to be largely an issue of rising levels of forms of oxidized and otherwise altered cholesterol, a consequence of oxidative stress and metabolic dysfunction in aged tissues. Macrophages are poorly equipped to process altered cholesterol, and become overwhelmed and inflammatory. Another contributing issue is a rising level of background inflammation, caused by immune system reactions to signs of age-related molecular damage in the body, among other causes. Macrophages can adopt different behaviors depending on their environment: the M2 phenotype is suitable for clearing out cholesterol from blood vessel walls, but inflammatory signaling provokes macrophages into the M1 phenotype instead.

The result is that atherosclerotic plaques become inflammatory hotspots of dysfunctional, dying macrophages. Their distressed signaling calls in more macrophages, forming a positive feedback loop that will proceed once established regardless of levels of LDL cholesterol in the bloodstream. Lowering LDL cholesterol takes some of the pressure off macrophages, and can result in a reduction of lipids in the worst plaques, but it has only a limited success in reducing mortality precisely because it doesn't reverse development of plaques to a meaningful degree. To do better than this, the macrophages must be rescued, made invulnerable (or at least more resilient) to the factors causing them to become dysfunctional. If macrophages in old tissues worked in the same was as they do in young tissues, there would be no atherosclerosis. Both Underdog Pharmaceuticals and Repair Biotechnologies are working on approaches to this goal.

A number of research groups also work towards improving macrophage function as an approach to the treatment of atherosclerosis, but not all such efforts are likely to be meaningfully effective. Metformin, for example, the subject of today's open access paper, influences some mechanisms of interest, such as those relating to inflammatory signaling. We know what the outcomes of metformin use on mortality are in humans, however, and they are certainly not good enough to justify a strong focus on this drug. Whether it can point the way to more effective treatments that target the same signaling mechanisms is an open question.

Metformin, Macrophage Dysfunction and Atherosclerosis

Metformin is one of the most widely prescribed hypoglycemic drugs and has the potential to treat many diseases. More and more evidence shows that metformin can regulate the function of macrophages in atherosclerosis, including reducing the differentiation of monocytes and inhibiting the inflammation, oxidative stress, polarization, foam cell formation, and apoptosis of macrophages. The mechanisms by which metformin regulates the function of macrophages include AMPK, AMPK independent targets, NF-κB, ABCG5/8, Sirt1, FOXO1/FABP4, and HMGB1.

Macrophages, which are distributed in the circulation and tissues and aggregate under a variety of pathological conditions, can play an important role in a variety of diseases by regulating inflammation. Considerable evidence indicates that metformin can improve the dysfunction of macrophages which is a cause of atherosclerosis. We speculate that improving the function of macrophages may be the basis for the expanding therapeutic potential of metformin. Combined with other drugs that improve the function of macrophages (such as SGLT2 inhibitors, statins, and IL-β inhibitor), this may help to further strengthen the pleiotropic actions and thus the therapeutic potential of metformin.

In addition, there is evidence that metformin can inhibit the formation of neutrophil extracellular traps (NETs), which may be related to the effect of metformin on improving macrophage function. In terms of research depth, single-cell sequencing helps to further clarify the mechanism of metformin and help to discover new targets for improving the function of macrophages and controlling or reducing the role of these cells in multiple disease processes and states.

Cellular Senescence in the Context of Aging, Metabolism, and Epigenetics
https://www.fightaging.org/archives/2021/07/cellular-senescence-in-the-context-of-aging-metabolism-and-epigenetics/

The accumulation of senescent cells is clearly an important contribution to the progression of degenerative aging. This was firmly established to be the case not by the careful examination of mechanisms, because it is very challenging to assign relative significance to the many different processes involved in aging, but rather by the selective removal of senescent cells in mice. The best way, and possibly the only practical way at the present time, to establish the relevance of a mechanism to aging and disease is to very selectively block just that mechanism and then observe the results.

In the case of senescent cell removal, the outcome is a rapid rejuvenation of many aspects of aging. Senescent cells clearly actively maintain a disrupted state of metabolism and tissue function via the signals that they secrete. Remove that signaling, and tissues begin to return to a more youthful function. This can produce quite profound reversals. In mice, for example, ventricular hypertrophy, the distortion and weakening of heart muscle, is reversed by treatment with therapies capable of removing senescent cells. That is a surprising result, and one that might make us all more optimistic as to the degree to which rejuvenation therapies will be able to help people in later life.

A great deal of effort is presently going into understanding the biochemistry of cellular senescence, particularly regarding how it arises, meaning the various contributing factors that tip the balance of cell fate towards senescence. Many researchers are interested in preventing senescence, which may or may not prove to be a better way forward than periodic selective destruction of senescent cells. At least some cells become senescent for a good reason, in that they are damaged in ways that can raise the risk of cancer. Further, approaches based on minimizing the onset of senescence in cell populations have yet to produce animal studies anywhere near as impressive as the rejuvenation that results from clearance of senescent cells. But time will tell.

Inflammation, epigenetics, and metabolism converge to cell senescence and ageing: the regulation and intervention

Accumulating studies have proven the relationship between senescent cells and organismal ageing. Meanwhile, the concept of eliminating senescent cells to counteract ageing-related conditions has emerged and succeeded in rodent models. Researchers have found a large number of p16INK4a-positive senescent cells in various tissues that cause a range of ageing symptoms, including sarcopenia, cataracts, and lipodystrophy. Accordingly, targeted clearance of p16INK4a senescent cells alleviates the adverse symptoms and successfully extend the health span in many diseased models.

The field began to look for traces of senescent cells in common ageing diseases in humans, and successfully established a causal relationship between pathogenesis of ageing-related diseases and cell senescence. Take atherosclerosis as an example, we have known that plaques composed of fat and protein gradually accumulate on the inner arterial wall, which is prone to cause coronary atherosclerotic disease, stroke, or other ischemic severe diseases. Next, senescence-associated macrophages were recruited to the arterial wall, where the plaque initially formed. As time elapsed, other senescent cell types appeared near these sites. Compared with other control cells, these senescent cells expressed abundant secretory factors and metabolites that promoted the pathogenesis of atherosclerosis, concurrent with significant alterations in epigenetic imprints. Using a variety of approaches to remove these senescent cells attenuated the lesions, and thus alleviating the progress of atherosclerosis.

Consequently, focusing on the epigenetic and immunometabolic regulation of cell senescence may shed light on managing ageing-related diseases and therapeutic interventions. In this review, we highlight the recent advances in the understanding of the inflammatory, epigenetic, and metabolic basis of cell senescence, a comprehensive overview of relevant molecules and signaling pathways associated with cell senescence and organismal ageing are discussed. Finally, novel techniques and strategies intervening in the ageing process are briefly summarized.

Using Supercentenarian Data to Estimate Future Increases in Maximum Human Life Span
https://www.fightaging.org/archives/2021/07/using-supercentenarian-data-to-estimate-future-increases-in-maximum-human-life-span/

In today's research materials, scientists attempt to model future increases in maximum human longevity based on past data for supercentenarians, people aged 110 and older. This is an interesting exercise, but I think that all of the results have to be taken with a sizable grain of salt. Firstly, the data for extreme human outliers in longevity isn't great. A lot of it is of poor quality, and the portions that are well maintained do not include a sizable number of people. There are few survivors to such exceptional ages, which makes it hard to call any analysis of that data truly robust. This is a problem that afflicts all similar work on survival and longevity in the oldest individuals.

Secondly, and more importantly, extrapolating past trends in human longevity will tell us next to nothing about what will happen in the years ahead. Past trends in human life expectancy in late life are near entirely incidental, as none of the widely available approaches to treating age-related disease actually target the underlying causes of aging in any meaningful way. That is changing. There is now a longevity industry working on numerous forms of therapy that will slow or reverse the cell and tissue damage that causes aging. The use of senolytics to clear senescent cells will become widespread in the years to come. The old people of the 2030s will have a greatly reduced chronic inflammation and disruption of tissue function in comparison to those of today or past decades. That sort of night and day difference isn't accounted for by extrapolation of trends.

How long can a person live? The 21st century may see a record-breaker

The number of people who live past the age of 100 has been on the rise for decades, up to nearly half a million people worldwide. There are, however, far fewer "supercentenarians," people who live to age 110 or even longer. Such extreme longevity likely will continue to rise slowly by the end of this century, and estimates show that a lifespan of 125 years, or even 130 years, is possible. With ongoing research into aging, the prospects of future medical and scientific discoveries and the relatively small number of people to have verifiably reached age 110 or older, experts have debated the possible limits to what is referred to as the maximum reported age at death. While some scientists argue that disease and basic cell deterioration lead to a natural limit on human lifespan, others maintain there is no cap, as evidenced by record-breaking supercentenarians.

To calculate the probability of living past 110 - and to what age - researchers turned to the most recent iteration of the International Database on Longevity. That database tracks supercentenarians from 10 European countries, plus Canada, Japan and the United States. Using a Bayesian approach to estimate probability, the team created projections for the maximum reported age at death in all 13 countries from 2020 through 2100. Among their findings: there is near 100% probability that the current record of maximum reported age at death of 122 years will be broken; the probability remains strong of a person living longer, to 124 years old (99% probability) and even to 127 years old (68% probability); an even longer lifespan is possible but much less likely, with a 13% probability of someone living to age 130; it is "extremely unlikely" that someone would live to 135 in this century.

Probabilistic forecasting of maximum human lifespan by 2100 using Bayesian population projections

We use the exponential survival model for supercentenarians (people over age 110) but extend the forecasting window, quantify population uncertainty using Bayesian population projections, and incorporate the most recent data from the International Database on Longevity (IDL) to obtain unconditional estimates of the distribution of maximum reported age at death (MRAD) this century in a fully Bayesian analysis. Based on this analysis, there is a greater than 99% probability that the current MRAD of 122 will be broken by 2100. We estimate the probabilities that a person lives to at least age 126, 128, or 130 this century, as 89%, 44%, and 13%, respectively.

Disruption of Elastin in the Aging Skin, and the Little that Can Presently Be Done About It
https://www.fightaging.org/archives/2021/07/disruption-of-elastin-in-the-aging-skin-and-the-little-that-can-presently-be-done-about-it/

The flexibility of skin, and other elastic tissue such as blood vessel walls, depends upon the structural arrangement of elastin in the extracellular matrix. Elastin is largely laid down during the developmental period of life, and not much repaired thereafter. Disruption of this structure is progressive over time, and is a major contribution to the changing physical properties and appearance of aging skin. The effects on blood vessels and other internal tissues are more important: loss of elasticity in blood vessels cascades to cause a great deal of downstream damage and dysfunction via its effects on blood pressure, on development of atherosclerosis, on supply of nutrients to tissues, and so forth.

Repair of elastin is a challenging problem. One cannot just add elastin to a tissue and hope for improvement, as the precise structure, amount, and interactions with other components of the extracellular matrix are all important. The only realistic approach is to guide cells into performing the same work of elastic depositition that occurred in early life. This is not a solved problem, as it is quite possible to trigger behavior that leads to unhelpful or even harmful elastin deposition, in which the structure and amounts are incorrect. Regulatory networks must be clearly identified and then manipulated in the right ways.

Some therapies tested over the past few decades do manage to create some improvement in measures of tissue elasticity, with good evidence for this improvement to involve elastin deposition. The use of minoxidil, for example, was originally introduced as a way to treat age-related hypertension. The side-effects at the necessary doses are significant and health-threatening, however, such as cardiac edema. A great deal of work remains to produce a viable elastic deposition approach that could be widely used.

Clinical Relevance of Elastin in the Structure and Function of Skin

Elastin is the main component of elastic fibers, which provide stretch, recoil, and elasticity to the skin. Normal levels of elastic fiber production, organization, and integration with other cutaneous extracellular matrix proteins, proteoglycans, and glycosaminoglycans are integral to maintaining healthy skin structure, function, and youthful appearance. Although elastin has very low turnover, its production decreases after individuals reach maturity and it is susceptible to damage from many factors. With advancing age and exposure to environmental insults, elastic fibers degrade. This degradation contributes to the loss of the skin's structural integrity; combined with subcutaneous fat loss, this results in looser, sagging skin, causing undesirable changes in appearance.

The most dramatic changes occur in chronically sun-exposed skin, which displays sharply altered amounts and arrangements of cutaneous elastic fibers, decreased fine elastic fibers in the superficial dermis connecting to the epidermis, and replacement of the normal collagen-rich superficial dermis with abnormal clumps of solar elastosis material. Disruption of elastic fiber networks also leads to undesirable characteristics in wound healing, and the worsening structure and appearance of scars and stretch marks. Identifying ways to replenish elastin and elastic fibers should improve the skin's appearance, texture, resiliency, and wound-healing capabilities. However, few therapies are capable of repairing elastic fibers or substantially reorganizing the elastin/microfibril network.

Current intrinsic treatment modalities, which stimulate or modulate endogenous elastin, typically involve cosmetics and topical skincare products. However, given the complexity of tropoelastin production, assembly, and crosslinking, there is limited evidence that topical skincare products can reach the dermal layers of the skin or sufficiently stimulate elastin production.

Successful extrinsic treatment modalities to replenish elastin may require delivery of structurally intact tropoelastin or elastin; most experimental strategies have utilized elastin fragments that are inappropriate for in vivo elastin assembly. Proposed therapies for the connective tissue disorder cutis laxa provide other potential targets for restoring elastin. For example, although no specific treatments for cutis laxa exist, it has been suggested that the disordered elastic fiber assembly in this disease might be corrected by supplementing certain carrier molecules that have a role in the secretory pathways for elastolytic enzymes involved in elastin production. Other potential therapeutic strategies for increasing elastin production include stimulation of elastin gene expression. However, because tropoelastin expression and elastin production are substantially reduced in adult tissues, even large increases in their expression are unlikely to be physiologically relevant.

Considering tropoelastin is the main component of elastin, a more viable approach to repairing elastic fiber networks may be to use recombinant human tropoelastin-based treatments. The recombinant human tropoelastin may act as a substrate for skin fibroblasts to promote collagen production and glycosaminoglycan deposition, contributing to tissue repair and improved hydration in skin. A recent study showed that surgical delivery of exogenous tropoelastin via a collagen-based dermal substitute leads to the development of an extensive elastic fiber network in the deep dermis. Recombinant human tropoelastin has demonstrated early promise for wound repair, scar prevention and treatment, cosmetic applications, and aesthetics; it can be used by skin cells as a substrate to produce new elastic fibers. The applied use of tropoelastin for these indications is therefore a promising area of study.

The Redox-Senescence Axis in Aging
https://www.fightaging.org/archives/2021/07/the-redox-senescence-axis-in-aging/

The accumulation of senescent cells is an important cause of degenerative aging. These cells secrete a mix of signals that produces chronic inflammation and disrupts tissue maintenance and function. Researchers here note that oxidative stress and oxidative signaling appear to be important in cellular senescence. These aspects of cellular metabolism are influenced by many of the small molecule drugs that have been found to affect senescence, either by slowing the pace at which cells become senescent, or by selectively inducing apoptosis in senescent cells.

Myriad stress stimuli trigger the acquisition of senescence and/or its maintenance, which in addition to promoting tissue repair and remodeling also functions as an effector mechanism driving age-related pathologies. The functional dichotomy of senescence is visibly manifested in regulating signaling networks that suppress or promote the process of carcinogenesis and its progression. These biological responses are a function of the slew of cytokines and chemokines secreted by cells upon acquiring the senescence-associated secretory phenotype (SASP). Despite the current advancement in the understanding of various stimuli and signaling networks upstream and downstream of SASP, there is relative lack of clarity with respect to the temporo-spatial factors/events that govern the switch from the good (onco-suppressor) to the bad (oncogenic).

Importantly, the intricate crosstalk between senescence and cellular redox metabolism has potential therapeutic implications. To that end, it's worth pointing out that a majority of small molecule compounds with senomorphic and/or senolytic activities also elicit redox regulatory effects. The challenge obviously would be to untangle the inherent complexity of the redox-senescence interplay, which will inform the appropriate clinical utility of these strategies as well as selective repurposing of other drugs.

Could regulation of cellular redox status be the common denominator in senolytic and senomorphic strategies? In this regard, aside from the deleterious effects on bio-molecules, aberrant redox signaling, downstream of DNA damage response activation, could be critical in the maintenance of senescence, and as such restoring redox homeostasis could have the dual advantage of blocking the acquisition as well as maintenance of the senescent phenotype. Hence, one might dare to conjecture that, in addition to accumulating oxidant-mediated damage over time, ageing involves a further role for an aberrant redox microenvironment in promoting cellular senescence.

Overactive Monocytes and Macrophages Contribute to the Onset of Alzheimer's Disease
https://www.fightaging.org/archives/2021/07/overactive-monocytes-and-macrophages-contribute-to-the-onset-of-alzheimers-disease/

There is an increasing focus in the research community on the role of chronic inflammation in the development of Alzheimer's disease. With age, the background level of inflammatory signaling rises as the immune system constantly responds to signs of damage and dysfunction. Immune cells become overactive. In the case of the innate immune cells known as monocytes, that give rise to macrophages, an inflammatory background shifts their focus away from supporting processes of regeneration and tissue maintenance, and into a more aggressive and inflammatory state. This has detrimental effects on long-term health, and contributes to the onset of many different age-related conditions.

Alzheimer's disease (AD) is the most common neurodegenerative disease ultimately manifesting as clinical dementia. Despite considerable effort and ample experimental data, the role of neuroinflammation related to systemic inflammation is still unsettled. While the implication of microglia is well recognized, the exact contribution of peripheral monocytes and macrophages is still largely unknown, especially concerning their role in the various stages of AD.

AD develops over decades and its clinical manifestation is preceded by subjective memory complaints (SMC) and mild cognitive impairment (MCI); thus, the question arises how the peripheral innate immune response changes with the progression of the disease. To further investigate the roles of monocytes and macrophages in the progression of AD we assessed their phenotypes and functions in patients at SMC, MCI, and AD stages and compared them with cognitively healthy controls. We also conceptualised an idealised mathematical model to explain the functionality of monocytes/macrophages along the progression of the disease.

We show that there are distinct phenotypic and functional changes in monocyte and macrophage populations as the disease progresses. Higher free radical production upon stimulation could already be observed for the monocytes of SMC patients. The most striking results show that activation of peripheral monocytes (hyperactivation) is the strongest in the MCI group, at the prodromal stage of the disease. Monocytes exhibit significantly increased chemotaxis, free radical production, and cytokine production in response to TLR2 and TLR4 stimulation. Thus our data suggest that the peripheral innate immune system is activated during the progression from SMC through MCI to AD, with the highest levels of activation being in MCI subjects and the lowest in AD patients.

Combined Duration and Degree of Hypertension a Better Correlation with Cardiovascular Risk
https://www.fightaging.org/archives/2021/07/combined-duration-and-degree-of-hypertension-a-better-correlation-with-cardiovascular-risk/

In the past researchers have found that a combined consideration of both duration and degree of being overweight is a better reflection of long-term health risks than a measure of weight made of any single point in time. This is reflective of underlying processes that cause lasting damage. Analogously, researchers here show that measuring the duration and degree of high blood pressure, hypertension, produces better correlations with cardiovascular disease risk than single measures at a point in time. Raised blood pressure causes structural damage to delicate tissues, leads to cardiac hypertrophy, accelerates the development of atherosclerosis, and raises the risk of a weakened blood vessel or atheroma rupturing to produce a heart attack or stroke. Some of this is a matter of lasting harm that will persist after blood pressure is reduced, at least in the context of today's medical technologies and capabilities.

Cumulative blood pressure (BP), a measure incorporating the level and duration of BP exposure, is associated with the risk of cardiovascular disease (CVD). However, the level at which cumulative BP could significantly increase the risk remains unclear. This study aimed to investigate the association of 15-year cumulative BP levels with the long-term risk of CVD, and to examine whether the association is independent of BP levels at one examination.

Data from a 26-year follow-up of the Chinese Multi-provincial Cohort Study-Beijing Project were analyzed. Cumulative BP levels between 1992 and 2007 were calculated among 2429 participants free of CVD in 2007. Cardiovascular events (including coronary heart disease and stroke) occurring from 2007 to 2018 were registered. Adjusted hazard ratios (HRs) for CVD incidence associated with quartiles of cumulative systolic blood pressure (SBP) and diastolic blood pressure (DBP) were calculated.

Of the 2429 participants, 42.9% (1042) were men, and the mean age in 2007 was 62.1 ± 7.9 years. Totally, 207 CVD events occurred during the follow-up from 2007 to 2018. Participants with higher levels of cumulative SBP or DBP exhibited a higher incidence rate of CVD. Compared with the lowest quartile of cumulative SBP, the HR for CVD was 1.03, 1.69, and 2.20 for the second to the fourth quartile of cumulative SBP, and 1.46, 1.99, and 2.08 for the second to the fourth quartile of cumulative DBP, respectively.

In conclusion, our study demonstrated that elevated cumulative SBP or DBP was independently associated with increased risk of CVD in the Chinese population. Among participants with 15-year cumulative BP levels higher than the median, that is, 1970.8/1239.9 mmHg-year for cumulative SBP/DBP, which was equivalent to maintaining SBP/DBP level higher than 131/83 mmHg in 15 years, the CVD risk would increase significantly irrespective of whether or not the BP measurements at one examination was high. Our findings emphasize the importance of cumulative BP level in identifying individuals with high risk of CVD in the future.

Indoles Produced by the Gut Microbiome Increase Neurogenesis
https://www.fightaging.org/archives/2021/07/indoles-produced-by-the-gut-microbiome-increase-neurogenesis/

There is good evidence for butyrate produced by the gut microbiome to increase neurogenesis via upregulation of BDNF. Here researchers show that indoles produced by gut microbes, via processing of tryptophan, also result in the outcome of increased neurogenesis. The balance of microbial species in the gut microbiome changes with age in ways that reduce this production of beneficial metabolites, as well as increasing the activity of harmful species that provoke the immune system into chronic inflammation. The combination of these issues may be as influential as physical activity on long-term health, judging from the benefits produced in animal models via transplantation of a youthful microbiome into old individuals.

The billions of microbes living in your gut could play a key role in supporting the formation of new nerve cells in the adult brain, with the potential to possibly prevent memory loss in old age and help to repair and renew nerve cells after injury. Researchers found that gut microbes that metabolise tryptophan - an essential amino acid - secrete small molecules called indoles, which stimulate the development of new brain cells in adults.

The team also demonstrated that the indole-mediated signals elicit key regulatory factors known to be important for the formation of new adult neurons in the hippocampus, an area of the brain also associated with memory and learning. Memory loss is a common sign of accelerated ageing and often an early sign of the Alzheimer's disease (AD).

"This finding is exciting because it provides a mechanistic explanation of how gut-brain communication is translated into brain cell renewal, through gut microbe produced molecules stimulating the formation of new nerve cells in the adult brain. These findings bring us closer to the possibility of novel treatment options to slow down memory loss, which is a common problem with ageing and neurodegenerative diseases. These include drugs to mimic the action of indoles to stimulate the production of new neurons in the hippocampus or to replace neurons damaged by stroke and spinal injury, as well as designing dietary intervention using food products enriched with indoles as a preventive measure to slow down ageing,"

Tryptophan and Age-Related Changes in the Gut Microbiome
https://www.fightaging.org/archives/2021/07/tryptophan-and-age-related-changes-in-the-gut-microbiome/

Researchers here suggest that reduced tryptophan intake can change the balance of populations in the gut microbiome to favor inflammatory microbes. Diet in late life is often deficient, with consequences that can approach outright malnutrition. It seems unlikely that this is a major issue earlier in life, however, and the gut microbiome exhibits harmful shifts in composition as early as the mid-30s. The influence of changes in the gut microbiome on health may be in a similar range to those of exercise, so it is a topic of growing interest in the research community. Ways to preserve or reset the gut microbiome have been demonstrated in animal studies, such as flagellin immunization or fecal microbiota transplantation. Bringing these and other approaches into human medicine should be a priority, given the comparatively low cost and risk.

With age, a diet lacking in the essential amino acid tryptophan - which has a key role in our mood, energy level and immune response - makes the gut microbiome less protective and increases inflammation body-wide, investigators report. In a normally reciprocal relationship that appears to go awry with age, sufficient tryptophan helps keep our microbiota healthy. A healthy microbiota in turn helps ensure that tryptophan mainly results in good things for us like producing the neurotransmitter serotonin, which reduces depression risk, and melatonin, which aids a good night's sleep.

But in aged mice, just eight weeks on a low-tryptophan diet results in some unhealthy changes in the trillions of bacteria that comprise the gut microbiota and higher levels of systemic inflammation. For example, when tryptophan levels are low, the investigators found lower levels of Clostridium, the bacterium that metabolizes the essential amino acid enabling production of good products like serotonin in the gut, and a threefold increase in the bacterium Acetatifactor, which is associated with intestinal inflammation.

The unhealthy changes they saw in the microbiota made researchers also suspect increased release of inflammation-promoting signaling molecules called cytokines, hypothesizing that microbiota changes might induce release of the molecules body-wide. They looked specifically at the largely inflammation-promoting IL-17 and IL-1a as well as IL-6 and IL-27, which can both promote and suppress inflammation, in the blood of mice on a low tryptophan diet. They found significant increases of IL-6, IL-17A and IL-1a and a significant decrease in IL-27, a cytokine which prevents transcription of inflammation-invoking IL-17 and helps do things like increase regulatory T cells in the gut, which suppress inflammation. Conversely, mice on a tryptophan-rich diet had higher levels of the calming IL-27.

When the aged mice resumed a healthy tryptophan intake, some of the unhealthy changes resolved in just a few days. But the reality that just increasing tryptophan did not always correct problems, and that some tryptophan metabolites are actually harmful, provides more evidence that a better option is giving select metabolites early on to help keep the microbiota functioning optimally, rather than attempting a tryptophan rescue.

Applying Chimeric Receptor Antigens to Natural Killer Cells to Target Solid Cancers
https://www.fightaging.org/archives/2021/07/applying-chimeric-receptor-antigens-to-natural-killer-cells-to-target-solid-cancers/

Chimeric antigen receptor (CAR) technology was first applied to T cells of the adaptive immune system. A patient's T cells are extracted, engineered to express a surface feature that matches to the patient's cancer cells, expanded in culture, and introduced back into the body. This has proven to be highly effective against forms of leukemia. Researchers are attempting to apply this approach to other varieties of immune cell, and thus allow a greater range of efficacy against various classes of cancer. Here, researchers report on their efforts to engineer natural killer cells to recognize patient cancers.

Modified natural killer (NK) cells can differentiate between cancer cells and healthy cells. The experimental treatment is an alternative to chimeric antigen receptor T-cell therapy, or CAR-T. The engineered T-cells used in CAR-T therapy are highly effective against some blood-borne cancers but cannot distinguish between cancerous and non-cancerous cells. So while they offer important benefits, they are not uniformly applicable to all forms of cancer. In patients with solid tumors, the T-cells can cause devastating, even lethal side effects.

The team behind the research wanted a treatment with the same power as CAR-T, but which could be used safely against solid-tumor cancers. They first propagated natural killer cells taken from the blood of patients with breast cancer. Such cells perform a similar function to T-cells in the immune system. The researchers then genetically modified them to target specific receptors on cancer cells, successfully testing the CAR-NK cells in the laboratory on tumor cells derived from breast cancer patients

"The efficacy we see with CAR-NK cells in the laboratory is very promising and seeing that this technology is feasible is very important. Now, we have much better and safer options for solid tumors. These CAR-NK cells are a little bit smarter, in a way, in that they only kill the enemy cells and not good cells that happen to have the same marker. These engineered CAR-NK cells are an important step towards having a viable immunotherapy option in this large group of patients."

Epigenetic Rejuvenation During Embryogenesis
https://www.fightaging.org/archives/2021/07/epigenetic-rejuvenation-during-embryogenesis/

It is well established that early embryonic development involves a process of rejuvenation. As much as possible of the molecular damage characteristic of adult cells is stripped away. The development of cellular reprogramming to produce induced pluripotent stem cells has provided researchers with additional insight into some of this mechanisms of this process of embryonic rejuvenation, such as the resetting of epigenetic patterns and restoration of mitochondrial function. Using epigenetic clocks to assess embryonic cells at various stages of development produces interesting results, as shown here.

Aging is characterized by a progressive accumulation of damage, leading to the loss of physiological integrity, impaired function, and increased vulnerability to death. While the aging process affects the entire organism, it is often discussed that the germ line does not age, because this lineage is immortal in the sense that the germ line has reproduced indefinitely since the beginning of life. This notion dates to the 19th century when August Weismann proposed the separation of the ageless germ line and aging body.

However, being in the metabolically active state for two decades or more before its contribution to the offspring, the human germ line accumulates molecular damage, such as modified long-lived proteins, epimutations, metabolic by-products, and other age-related deleterious changes. It was shown that sperm cells exhibit a distinct pattern of age-associated changes. Accordingly, it was recently proposed that germline cells may age and be rejuvenated in the offspring after conception. If this is the case, there must be a point (or period) of the lowest biological age (here, referred to as the ground zero) during the initial phases of embryogenesis. Here, we carried out a quantitative, data-driven test of this idea.

We developed a multi-tissue epigenetic clock and applied it, together with other aging clocks, to track changes in biological age during mouse and human prenatal development. This analysis revealed a significant decrease in biological age, i.e., rejuvenation, during early stages of embryogenesis, followed by an increase in later stages. We further found that pluripotent stem cells do not age even after extensive passaging and that the examined epigenetic age dynamics is conserved across species. Overall, this study uncovers a natural rejuvenation event during embryogenesis and suggests that the minimal biological age (ground zero) marks the beginning of organismal aging.

Cellular Processes Involved in Brain Aging
https://www.fightaging.org/archives/2021/07/cellular-processes-involved-in-brain-aging/

The paper here is a representative example of much of the mainstream of research into aging, in that it is focused on processes that are well downstream of the causes of aging. In effect they are mechanistic symptoms of aging, the taxonomy of disruptions to the normal operation of cells and tissues that is the result of the underlying processes of damage accumulation that drive aging. It is likely that focusing on downstream outcomes of aging will result in an expensive path to poor therapies, at least in comparison to a focus on the underlying causes of these outcomes. The results of damage are more complicated to understand and address than the damage itself. Further, preventing the outcomes of damage without actually trying to repair the damage itself is likely to be somewhere between hard and impossible to achieve.

Aging is the leading risk factor for several age-associated diseases such as neurodegenerative diseases. Understanding the biology of aging mechanisms is essential to the pursuit of brain health. In this regard, brain aging is defined by a gradual decrease in neurophysiological functions, impaired adaptive neuroplasticity, dysregulation of neuronal Ca2+ homeostasis, neuroinflammation, and oxidatively modified molecules and organelles.

Numerous pathways lead to brain aging, including increased oxidative stress, inflammation, disturbances in energy metabolism such as deregulated autophagy, mitochondrial dysfunction, and IGF-1, mTOR, ROS, AMPK, SIRTs, and p53 as central modulators of the metabolic control, connecting aging to the pathways, which lead to neurodegenerative disorders.

Also, calorie restriction (CR), physical exercise, and mental activities can extend lifespan and increase nervous system resistance to age-associated neurodegenerative diseases. The neuroprotective effect of CR involves increased protection against ROS generation, maintenance of cellular Ca2+ homeostasis, and inhibition of apoptosis. The recent evidence about the modem molecular and cellular methods in neurobiology to brain aging is exhibiting a significant potential in brain cells for adaptation to aging and resistance to neurodegenerative disorders.

Glucose Metabolism Becomes Insufficient to Meet the Energy Demands of the Aging Hippocampus
https://www.fightaging.org/archives/2021/07/glucose-metabolism-becomes-insufficient-to-meet-the-energy-demands-of-the-aging-hippocampus/

Recent research has suggested that the hippocampus, vital to memory function, has evolved to operate at the upper edge of its normal supply of nutrients and energy. Even minor reductions to that supply will produce functional issues in memory, and there are many mechanisms by which aging reduces the supply of nutrients and energy to the brain. Reduced blood flow is one important factor, due to loss of capillary density, vascular dysfunction, lack of fitness, heart failure, and so forth. The paper here is an interesting read in this context, looking at loss of efficiency in glucose metabolism in the aging hippocampus. The brain obtains most of its energy from processing of glucose, and disruption might be expected to produce negative consequences.

Aging is a process that adversely affects brain functions such as cognition. Brain activity is highly energy consuming, with glucose serving as the main energy source under normal circumstances. Whether the dynamics of glucose metabolism change with aging is not well understood. This study sought to investigate the activity-dependent changes in glucose metabolism of the mouse hippocampus during aging. In brief, after 1 hour of contextual exploration in an enriched environmental condition or 1 hour in a familiar home cage condition, metabolites were measured from the hippocampus of both young adult and aged mice with metabolomic profiling.

Compared to the home cage context, enriched contextual exploration resulted in changes in the concentration of 11 glucose metabolism-related metabolites in the young adult hippocampus. In contrast, glucose metabolism-related metabolite changes were more apparent in the aged group altered by contextual exploration when compared to those in the home cage condition. Importantly, in the aged groups, several key metabolites involved in glycolysis, the TCA cycle, and ketone body metabolism accumulated, suggesting the less efficient metabolization of glucose-based energy resources. Altogether, the analyses revealed that in the aged mice altered by enriched contextual exploration, the glucose resource seems to be unable to provide enough energy for hippocampal function.

Delivery of α-klotho as a Basis for Neuroprotective Treatments
https://www.fightaging.org/archives/2021/07/delivery-of-%ce%b1-klotho-as-a-basis-for-neuroprotective-treatments/

Klotho is one of the few well-established longevity-associated genes that works in both directions in animal models: less klotho shortens life span, while more klotho extends life. Klotho also improves cognitive function. The mechanisms by which klotho produces these outcomes remain poorly understood: there is the usual grab-bag of identified mechanisms, and little idea as to which are more or less important than the others, or as to whether the list is even near complete. In recent years, research results have indicated that klotho likely undertakes its important functions in the kidneys rather than the brain, and its effects are a reflection of the importance of kidney function to the body as a whole. Meanwhile, delivery of soluble α-klotho has been shown to be beneficial in mice, and some groups are presently in the early stages of developing this approach as a therapy for neurodegenerative conditions.

Cognitive dysfunction is a key symptom of ageing and neurodegenerative disorders, such as Alzheimer's disease (AD). Strategies to enhance cognition would impact the quality of life for a significant proportion of the ageing population. The α-klotho protein may protect against cognitive decline through multiple mechanisms: such as promoting optimal synaptic function via activation of N-methyl-d-aspartate (NMDA) receptor signalling; stimulating the antioxidant defence system; reducing inflammation; promoting autophagy and enhancing clearance of amyloid-β.

However, the molecular and cellular pathways by which α-klotho mediates these neuroprotective functions have yet to be fully elucidated. Key questions remain unanswered: which form of α-klotho (transmembrane, soluble, or secreted) mediates its cognitive enhancing properties; what is the neuronal receptor for α-klotho and which signalling pathways are activated by α-klotho in the brain to enhance cognition; how does peripherally administered α-klotho mediate neuroprotection; and what is the molecular basis for the beneficial effect of the VS polymorphism of α-klotho?

In this review, we summarise the recent research on neuronal α-klotho and discuss how the neuroprotective properties of α-klotho could be exploited to tackle age- and neurodegeneration-associated cognitive dysfunction.