Fight Aging!

Robust modern forms of vaccination that were developed in the 20th century remain one of the most important forms of medical technology. Infectious diseases are not going away any time soon, and continue to cause a sizable fraction of human mortality, even though that fraction is much reduced in our era. Unfortunately, effective vaccination depends on an effective immune system, and thus vaccines tend to perform increasingly poorly with advancing age. As we age our immune system becomes ever less capable, a decline into immunosenescence caused by a range of contributing processes: involution of the thymus, where T cells of the adaptive immune system mature; a growing presence of senescent, exhausted, and malfunctioning immune cells; a shift in cell populations of the bone marrow to produce more myeloid and fewer lymphoid cells; and so forth.

As today's open access paper points out, the approach to improving vaccination in the old has long been to find ways to work around the growing incapacity of the aged immune system. Developing better adjuvants to vaccines, for example. This produces only incremental gains. The yearly toll of influenza deaths is much larger than the estimates of prevented deaths due to widespread vaccination. For the 2022-2023 season those numbers show 21,000 estimated deaths versus 3,600 estimated prevented deaths. Most of those deaths are old people, not only less able to defend against an infectious pathogen, but also less able to benefit from vaccination. Something must change! That change must be to focus on ways to repair the aged immune system, restore its function to more youthful capabilities.

There are any number of approaches presently under development that show promise. Restoration of active thymic tissue would help by providing a supply of new T cells. Use of CASIN can produce lasting improvements in hematopoietic stem cell function in the bone marrow following a single treatment. Clearance of populations of malfunctioning immune cells has been demonstrated to improve immune function in animal models. Clearance of senescent cells can reduce the burden of unresolved inflammatory signaling that puts stress on the aged immune system. There are more in various stages of development.

Insights into vaccines for elderly individuals: from the impacts of immunosenescence to delivery strategies

The global population is entering an era of aging. Older people are more susceptible to pathogens and have higher rates of morbidity and mortality. Despite the significant success of current vaccine products, many commercial vaccines fail to generate effective and long-lasting immune protection in elderly individuals. With increasing age, the reasons for the decline in vaccine potency are multifactorial. Age-related dysregulation of lymph nodes, and crucial immune cells jointly reduces the efficiency of vaccination. With the continuous emergence of new pathogens, it is urgent to create strategies to improve vaccination-mediated protection for elderly individuals.

The existing approaches are primarily aimed at optimizing the vaccine delivery system rather than inhibiting the immunosenescence of the immune microenvironment in elderly individuals. Inhibiting the immunosenescence of elderly individuals can evoke strong and long-lasting immune protection, which serves as a critical measure to improve vaccine-induced immunity. Although inhibition of immunosenescence most likely requires continuous intervention/treatment and is complicated to achieve, we believe that sustained-release vaccination/adjuvants or booster immunizations may sustainably ameliorate immunosenescence in the elderly. Once the immunosenescence of the elderly is corrected, their immune efficacy against various antigens can be improved.

An attractive research direction will be discovering immunomodulators and vaccine formulations that can inhibit immunosenescence. The selection of adjuvants can greatly impact the type and magnitude of the immune response. Considering the special immune status of elderly individuals, designing tailored vaccine adjuvants is indispensable for the development of next-generation vaccines for older individuals. A chronic inflammatory state also accompanies immunosenescence. However, the common opinion is that adjuvants promote immunity by inducing local inflammation. Therefore, more in-depth studies are needed to explain the role of inflammation in vaccine-induced immunity and tune the contradictory perspectives.

Most studies focus on one or several cell types or certain processes of the immune response. However, our immune system is a complex and coordinated comprehensive network. More new technologies and advances will help reveal the complexity underlying the human immune system. We must pay more attention to the impacts of versatile cells or multiple immune cascade processes. Future research should focus on developing scientific methods to build more convincing models of aging and study the profound mechanisms underlying age-related alterations that impact the immune responses of older people.

One the important themes of the research and development at Repair Biotechnologies is that localized excesses of cholesterol arise with age, leading to excess intracellular cholesterol, which is a pathological mechanism that disrupts cell behavior and kills cells. Getting rid of these localized excesses of cholesterol is challenging, however, unless resorting to some form of engineered protein machinery or gene therapy. Cells cannot break down cholesterol and there is no good way to bind enough of the excess cholesterol to some form of small molecule for sequestration and disposal without also targeting vital cholesterol in cell membranes and elsewhere. As this paper notes, excess cholesterol is clearly a meaningful problem in aging.

Although dysregulated cholesterol metabolism predisposes aging tissues to inflammation and a plethora of diseases, the underlying molecular mechanism remains poorly defined. Here, we show that metabolic and genotoxic stresses, convergently acting through liver X nuclear receptor, upregulate CD38 to promote lysosomal cholesterol efflux, leading to nicotinamide adenine dinucleotide (NAD+) depletion in macrophages. Cholesterol-mediated NAD+ depletion induces macrophage senescence, promoting key features of age-related macular degeneration (AMD), including subretinal lipid deposition and neurodegeneration.

NAD+ augmentation reverses cellular senescence and macrophage dysfunction, preventing the development of AMD phenotype. Genetic and pharmacological senolysis protect against the development of AMD and neurodegeneration. Subretinal administration of healthy macrophages promotes the clearance of senescent macrophages, reversing the AMD disease burden. Thus, NAD+ deficit induced by excess intracellular cholesterol is the converging mechanism of macrophage senescence and a causal process underlying age-related neurodegeneration.

Link: https://doi.org/10.1016/j.celrep.2024.114102

Improved autophagy is implicated in many of the approaches shown to slow aging in animal models. An open question is whether more targeted approaches to altering the regulation of autophagy in aged cells can improve matters to a greater degree than, for example, exercise or the practice of calorie restriction, both of which are known to produce general improvements in autophagy. Researchers here show that improvement of autophagy via increased expression of TRP53INP2 in old mice can reduce the age-related loss muscle mass and function that leads to sarcopenia. It seems an interesting target for further development of therapies.

Sarcopenia is a major contributor to disability in older adults, and thus, it is key to elucidate the mechanisms underlying its development. Increasing evidence suggests that impaired macroautophagy/autophagy contributes to the development of sarcopenia. However, the mechanisms leading to reduced autophagy during aging remain largely unexplored, and whether autophagy activation protects from sarcopenia has not been fully addressed.

Here we show that the autophagy regulator TP53INP2/TRP53INP2 is decreased during aging in mouse and human skeletal muscle. Importantly, chronic activation of autophagy by muscle-specific overexpression of TRP53INP2 prevents sarcopenia and the decline of muscle function in mice. Acute re-expression of TRP53INP2 in aged mice also improves muscle atrophy, enhances mitophagy, and reduces reactive oxygen species (ROS) production. In humans, high levels of TP53INP2 in muscle are associated with increased muscle strength and healthy aging. Our findings highlight the relevance of an active muscle autophagy in the maintenance of muscle mass and prevention of sarcopenia.

Link: https://doi.org/10.1080/15548627.2024.2333717

The Targeting Aging with Metformin (TAME) clinical trial has been a feature of the divide between regulators, researchers, and industry in the matter of treating aging as a medical condition for as about as long as the longevity industry has existed. Regulators such as the FDA do not consider aging to be a disease, and they only approve treatments for specific diseases, largely using the World Health Organization's International Classification of Diseases as the basis for what is and is not a disease. The TAME trial came into being as a way to convince the FDA to approve a treatment on the basis of endpoints that approximated aging, rather than a disease.

In that sense the heavy lifting has been accomplished: the FDA indeed agreed with the TAME trial design, and so in principle anyone else with deep pockets could now adopt the same approach if they wanted to stand behind a treatment for aging. The biotech industry and those who fund it are highly conservative, however. Companies working on therapies that can in principle slow or reverse aspects of aging have all chosen to pick one or more specific age-related diseases, and quietly plan for off-label use following approval, as it is unlikely that they could otherwise have convinced investors to back their clinical and regulatory development.

As today's popular science article notes, the TAME trial remains incompletely funded. This, I suspect is the case in large part because metformin is a poor choice of treatment. It was selected because it is so very widely used, for so long, and with such an abundance of safety data, that the FDA could not possibly object on those grounds. Hindsight is 20/20, but rapamycin would be been a much better choice. The evidence for metformin to slow aging is not great. The animal data is mixed, to say the least, and the human data from studies of type 2 diabetes patients has a great many issues. Rapamycin more clearly slows aging, the animal data is robust, and human evidence shows minimal to no side-effects at the dose for anti-aging use. Still, here we are: it remains unclear as to whether the TAME trial will be completed, or be overtaken by events. The evolution of regulation with regards to the treatment of aging will likely shift to a battle over widespread off-label use as the first longevity industry therapies are approved for specific disease.

A cheap drug may slow down aging. A study will determine if it works

Metformin was first used to treat diabetes in the 1950s in France. The FDA approved metformin for the treatment of type 2 diabetes in the U.S. in the 1990s. Since then, researchers have documented several surprises, including a reduced risk of cancer. As promising as this sounds, most of the evidence is observational, pointing only to an association between metformin and the reduced risk. The evidence stops short of proving cause and effect. Also, it's unknown if the benefits documented in people with diabetes will also reduce the risk of age-related diseases in healthy, older adults.

Back in 2015, a bunch of aging researchers began pushing for a clinical trial. "A bunch of us went to the FDA to ask them to approve a trial for metformin, and the agency was receptive. If you could help prevent multiple problems at the same time, like we think metformin may do, then that's almost the ultimate in preventative medicine." The aim is to enroll 3,000 people between the ages of 65 and 79 for a six-year trial. But it's been slow going to get it funded. "The main obstacle with funding this study is that metformin is a generic drug, so no pharmaceutical company is standing to make money."

Researchers have turned to philanthropists and foundations, and has some pledges. The National Institute on Aging, part of the National Institutes of Health, set aside about $5 million for the research, but that's not enough to pay for the study which is estimated to cost between $45 and $70 million. The frustration over the lack of funding is that if the trial points to protective effects, millions of people could benefit. Currently the FDA doesn't recognize aging as a disease to treat, but the researchers hope this would usher in a paradigm shift - from treating each age-related medical condition separately, to treating these conditions together, by targeting aging itself.

This open access review paper covers the high points of what is presently known of the contribution of senescent cells to neurodegenerative conditions. Somatic cells become senescent throughout life, largely as they reach the Hayflick limit to replication, but also due to damage or a toxic local environment. Senescent cells halt replication and begin to secrete pro-inflammatory signals to attract the immune system. In youth, senescent cells are rapidly cleared by programmed cell death or by immune cells. With age, the immune system becomes less efficient. As a consequence senescent cells begin to accumulate, and they help to generate a state of chronic inflammation and tissue dysfunction, contributing to the onset and progression of age-related disease.

Cellular senescence is a ubiquitous process and is a state of irreversible cell cycle arrest, induced by a variety of cellular stimuli such as DNA damage, telomere shortening/dysfunction, oncogenic activation and chromatin disruption. Cellular senescence limits the replicative lifespan of cells and contributes to aging and age-related diseases. Senescent cells resist apoptosis and secrete persistent pro-inflammatory signals that are fatal to neighboring cells.

Neurodegenerative disease are characterized by chronic, progressive and pathological changes in the brain, such as neuronal death, abnormal aggregation of proteins and inflammation. Recent evidences suggest that the pathological changes in the neurodegenerative disease begins much ahead of the actual appearance of the symptoms. Prolonged exposure to stress such as DNA damage may induce cellular senescence and contribute to the pathogenesis of the disease by altering metabolism and affecting gene expression.

Alzheimer's disease accumulates toxic protein aggregates in the brain, including amyloid-beta plaques and tau tangles. Recent studies have shown that cellular senescence plays a role in developing and accumulating these toxic protein aggregates. As evidenced by increased SA-β-gal expression, p53 expression, a mediator of cellular senescence, an increase in the release of senescence-associated secretory phenotype (SASP) components, DNA damage, telomere attrition or damage, and senescence-like morphological changes, increased senescence is found in various cell types of Alzheimer's disease brains, including astrocytes, microglia, and neurons. In 2018 researchers found that cellular senescence is associated with tau protein aggregation in the brain. The researchers combined genomic analysis with pharmacological interventions to induce senescence in neurons, which led to increased tau aggregation and neuronal dysfunction. Conversely, clearance of senescent cells reduced tau-dependent pathology.

Parkinson's disease (PD) is the most common movement disorder and the second most prevalent neurodegenerative disease after Alzheimer's disease. Pre-symptomatic midbrain inflammation plays a crucial role in the pathology of PD. Cellular senescence triggers a pro-inflammatory response, the SASP, so senescence and SASP together are a strong contributing factor in the pathophysiology of PD. The dopaminergic (DA) neurons in PD has been noted to express various senescence markers. Neuronal senescence has also been recognized to contribute to the "inflammaging" seen in PD. In a recent study, it was found that α-synuclein (α-syn) aggregates triggers stress induced premature senescence in PD models. α-syn preformed fibrils triggers cellular senescence in astrocytes and microglia and leads to their activation. Overactivation of microglia has been detected in PD patients. Microglia when activated produce inflammatory products which might contribute to the dopaminergic neuronal death in PD patients.

Link: https://doi.org/10.3389/fragi.2023.1292053

There is a bidirectional relationship between declining kidney function and raised blood pressure, two prominent features of aging. The kidney is responsible for managing blood volume (one contribution to blood pressure) by adjusting the amount of water in blood as the bloodstream is filtered, a process that depends on some combination of the sensing of soluble factors and pressure. These complex systems fail with age in ways that can lead to raised blood pressure. Raised blood pressure in turn can damage the kidney directly, but also indirectly disrupt the balance of blood pressure control systems elsewhere in the body, such as via the constriction and dilation of blood vessels, or heart rate, that interact with those of the kidney via signaling molecules. It is a complex set of feedback loops, well-balanced in youth, but prone to damage that can cause a spiral into ever high blood pressure with advancing age.

Cardiovascular diseases affect kidney function. The aim of this study was to investigate the possible associations between hemodynamic parameters and change in kidney function in individuals aged 75 years and older. Data on hemodynamics and blood and urine samples were collected at baseline and during one-year visits. Hemodynamics were split into two groups based on median values. Changes in the estimated glomerular filtration rate (eGFR) were investigated between low and high groups for each hemodynamic parameter using analysis of variance. Changes in the albumin-creatinine ratio (ACR) were examined as binary outcomes (large increase vs. stable) using logistic regression.

The study population consisted of 252 participants. Participants in the high central systolic blood pressure (cSBP) group had a greater decline in eGFR than participants in the low cSBP group (-6.3% vs. -2.7%). Participants in the high aortic pulse wave velocity (aPWV) group, indicative of greater arterial stiffness, had a greater decline in eGFR than those in the low aPWV group (-6.8% vs. -2.5%). Other hemodynamic parameters were not associated with eGFR changes.

In conclusion, we found that elevated central aortic stiffness is associated with a greater decline in kidney function in old age. Since aPWV and cSBP both appear to be predictors of eGFR decline, it might be of interest to identify older individuals with elevated aortic stiffness. In this specific population, intensive blood pressure reduction might be justified in order to slow down the process of vascular aging and prevent kidney function decline.

Link: https://doi.org/10.3390/jcm13051334

It is well known that metabolic dysfunction and cardiovascular disease correlate well with an accelerated onset and progression of neurodegenerative conditions. This is particularly evident when considering these conditions in the context of obesity. Age-related diseases are the late stage consequences of a progressive accumulation of cell and tissue damage, and so a lifestyle that accelerates those underlying damage processes will produce a greater incidence of all of the common age-related diseases. Suffering from one form of age-related disease thus implies greater odds of suffering other forms of age-related disease, as they all descend from the same roots.

As demonstrated in today's open access paper, it isn't just the end result of outright dementia that correlates with the presence of other forms of age-relate disease. Suffering from metabolic or cardiovascular disease clearly correlates with the earlier stages of brain aging as well, such as cognitive decline, measures of brain volume, and the presence of small white matter hyperintensities that result from ruptured capillaries in brain tissue. Some of these harms derive from the underlying forms of damage that cause age-related disease, others are downstream of vascular aging or the inflammation of metabolic disease, others are a mix.

Cardiometabolic disease, cognitive decline, and brain structure in middle and older age

Cardiometabolic diseases (CMDs), a cluster of related conditions including type 2 diabetes (T2D), heart disease (HD), and stroke, are well-established individual risk factors for cognitive/brain aging and dementia. Cardiometabolic multimorbidity - the coexistence of ≥ 2 CMDs in the same individual - has risen greatly with population aging and is estimated to affect up to 30% of older adults. Recent studies have described a dose-dependent increase in dementia risk with one, two, and three co-morbid CMDs. However, less is known about the combined influence of CMDs on the subtle cognitive decline and brain structural changes that can occur in the decades before dementia diagnosis.

Brain magnetic resonance imaging (MRI) studies have linked cardiometabolic multimorbidity and unfavorable cardiovascular risk profiles to lower volumes of subcortical structures and poorer white matter microstructural integrity in older age. Moreover, recent studies suggest that cardiovascular and metabolic risk factors could be associated with vascular lesions already in middle age. However, evidence is lacking on the relationship between cardiometabolic multimorbidity and brain structure at different stages of life.

In the present study, using longitudinal data from adults that were middle-aged, younger than 60 years, as well as individuals older than 60 years in the UK Biobank, we aimed to (1) assess the association between cardiometabolic multimorbidity and changes in global and domain-specific cognitive function and (2) identify the brain regions that are possibly associated with cardiometabolic multimorbidity in middle and older age. 46,562 dementia-free UK Biobank participants completed a cognitive test battery at baseline and a follow-up visit 9 years later, at which point 39,306 also underwent brain magnetic resonance imaging. CMDs were ascertained from medical records.

A higher number of CMDs was associated with significantly steeper global cognitive decline in the older but not middle aged cohort. Additionally, the presence of multiple CMDs was related to smaller total brain volume, gray matter volume, white matter volume, hippocampal volume, and larger white matter hyperintensity volume, even in middle age. Thus CMDs are associated with cognitive decline in older age and worse brain structural health beginning already in middle age.

There has long been a school of thought on Alzheimer's disease that consideres it a form of diabetes, in which dysregulated glucose metabolism features prominently. This dysregulation certainly occurs; the study noted here isn't the only one to show that the aging brain no longer manages glucose adequately. The question is whether this mechanism is important relative to all of the other processes thought to contribute to the pathology of Alzheimer's disease and other neurodegenerative conditions, and where it fits in a chain of cause and consequence. Finding ways to demonstrate the relative importance of different mechanisms remains the primary challenge in developing a sufficient understanding of aging and age-related disease to make rapid progress towards effective therapies.

Defective brain glucose utilization is a hallmark of Alzheimer's disease (AD) while Type II diabetes and elevated blood glucose escalate the risk for AD in later life. Isolating contributions of normal aging from coincident metabolic or brain diseases could lead to refined approaches to manage specific health risks and optimize treatments targeted to susceptible older individuals.

We evaluated metabolic, neuroendocrine, and neurobiological differences between young adult (6 months) and aged (24 months) male rats. Compared to young adults, blood glucose was significantly greater in aged rats at the start of the dark phase of the day but not during the light phase. When challenged with physical restraint, a potent stressor, aged rats effected no change in blood glucose whereas blood glucose increased in young adults. Tissues were evaluated for markers of oxidative phosphorylation (OXPHOS), neuronal glucose transport, and synapses.

Outright differences in protein levels between age groups were not evident, but circadian blood glucose was inversely related to OXPHOS proteins in hippocampal synaptosomes, independent of age. The neuronal glucose transporter, GLUT3, was positively associated with circadian blood glucose in young adults whereas aged rats tended to show the opposite trend. Our data demonstrate aging increases daily fluctuations in blood glucose and, at the level of individual differences, negatively associates with proteins related to synaptic OXPHOS. Our findings imply that glucose dyshomeostasis may exacerbate metabolic aspects of synaptic dysfunction that contribute to risk for age-related brain disorders.

Link: https://doi.org/10.1016/j.nbas.2024.100116

Because epigenetic clocks are produced from DNA methylation data via machine learning approaches, correlating patterns of change with chronological age, it remains unclear as to what exactly they measure. Which processes of aging produce the specific DNA methylation changes used in any given clock? As yet that question has no answer. Thus a discovery process continues, in which researchers uncover clock behaviors such as a dependency on aspects of the circadian rhythm. Determining exactly which aspects will be one small part of a much longer process of understanding the details of the relationship between DNA methylation and the rest of cellular biochemistry. For now it is a caveat for those using aging clocks, epigenetic or otherwise - either pick a clock demonstrated to lack this behavior, or be consistent in time of day when measuring.

Since their introduction, epigenetic clocks have been extensively used in aging, human disease, and rejuvenation studies. In this article, we report an intriguing pattern: epigenetic age predictions display a 24-hour periodicity. We tested a circadian blood sample collection using 17 epigenetic clocks addressing different aspects of aging. Thirteen clocks exhibited significant oscillations with the youngest and oldest age estimates around midnight and noon, respectively. In addition, daily oscillations were consistent with the changes of epigenetic age across different times of day observed in an independant populational dataset.

While these oscillations can in part be attributed to variations in white blood cell type composition, cell count correction methods might not fully resolve the issue. Furthermore, some epigenetic clocks exhibited 24-hour periodicity even in the purified fraction of neutrophils pointing at plausible contributions of intracellular epigenomic oscillations. Evidence for circadian variation in epigenetic clocks emphasizes the importance of the time-of-day for obtaining accurate estimates of epigenetic age.

Link: https://doi.org/10.1111/acel.14170

The hundreds of mitochondria found in every cell are in effect power plants, their primary task being to manufacture the chemical energy store molecule adenosine triphosphate (ATP), which is used to power cellular processes. Mitochondria become damaged like every cellular component, and are recycled frequently. With age, however, changes in expression of mitochondrial and other proteins lead to dysfunctional recycling and dysfunctional mitochondria. ATP production suffers, side-effects of ATP production such as the generation of free radical molecules grow to become problematic, and cell function is impacted. This happens throughout the body, and is thought to be an important contributing cause of degenerative aging.

At least two companies are working earnestly on developing mitochondrial transplantation therapies as a way to treat aging, Mitrix Bio and Cellvie Scientific. Cells will readily take up mitochondria from the surrounding environment. Studies in animals suggest that supplying fully functional mitochondria, harvested from cell cultures, to tissues in which mitochondria are dysfunction can fix the problem for long enough to be interesting as a basis for therapy. The primary challenges are (a) to understand whether mitochondrial haplotypes must match between donor and recipient, (b) cost-effective and reliable manufacture of large enough amounts of undamaged, function mitochondria, and (c) delivery to the harder-to-reach parts of the body. The companies are primarily engaged in the logistics of large-scale manufacture.

Today's open access paper is a compelling demonstration from researchers associated with Cellvie Scientific, demonstrating sizable gains in mitochondrial function, muscle function, and endurance in old mice resulting from direct injection of mitochondria into hindlimb muscles. The amount of mitochondria harvested and injected is reasonable from a manufacturing point of view if scaling up to human use. I expect these companies to initially target frailty, sarcopenia, and related conditions. I also expect the medical tourism community to begin to offer mitochondrial transplantation therapies on much the same timescale. Clinical businesses already have a great deal of experience in managing cell cultures and cell harvesting, and moving from there to harvesting mitochondria is an achievable goal. They have already achieved a similar shift in moving to the use of extracellular vesicles in therapy.

Mitochondrial Transplantation's Role in Rodent Skeletal Muscle Bioenergetics: Recharging the Engine of Aging

Cardiorespiratory fitness is a health indicator of all-cause mortality. One critical component of cardiorespiratory fitness is the function of mitochondria within the skeletal muscle which generates energy to perform exercise or activities of daily living. There is clear evidence that aging results in a reduction in mitochondrial function. Initially proposed as the mitochondrial theory of aging in the 1950s, age-related decreases in mitochondrial function have since been shown to play a major role in skeletal muscle decline. Not surprisingly, in regard to aging-related decline of skeletal muscle, mitochondrial oxidative capacity has been implicated in sarcopenia. Research suggests that the skeletal muscle of elderly individuals exhibits a rise in nonoperational mitochondria, an increase in mutated and deleted mitochondrial DNA with an associated decrease in mitochondrial density.

Non-exercise alternatives such as nutraceuticals or pharmacological agents to improve skeletal muscle bioenergetics act systemically and have resulted in moderate success. Nevertheless, these natural and pharmacological compounds have limitations, particularly in the duration of time (i.e., weeks or months) to induce beneficial molecular and cellular changes in skeletal muscle. Thus, the question arises: "Is there a faster, tissue targeted, and more effective approach to enhance skeletal muscle bioenergetics?"

Mitochondrial transplantation represents a novel therapy designed to enhance energy production of tissues impacted by defective mitochondria. This innovative approach involves transferring isolated mitochondria from either a donor to a host or from the host to itself. Initially used to attenuate the effects of ischemia-reperfusion injury in cardiac tissue transplanted mitochondria, which are rapidly purified and remain viable and capable of respiration, are directly injected into the target tissue. In skeletal muscle, mitochondrial transplantation has proven effective in enhancing hindlimb bioenergetics in various rodent models. Mitochondrial transplantation circumvents the limitations of both exercise and non-exercise interventions by directly delivering isolated mitochondria into the target tissue.

To date, no studies have used mitochondrial transplantation as an intervention to attenuate aging-induced skeletal muscle mitochondrial dysfunction. In this study 15 female mice (24 months old) were randomized into two groups (placebo or mitochondrial transplantation). Isolated mitochondria from a donor mouse of the same sex and age were transplanted into the hindlimb muscles of recipient mice. The results indicated significant increases (ranging between ~36% and ~65%) in basal cytochrome c oxidase and citrate synthase activity as well as ATP levels in mice receiving mitochondrial transplantation relative to the placebo. Moreover, there were significant increases (approximately two-fold) in protein expression of mitochondrial markers in both glycolytic and oxidative muscles. These enhancements in the muscle translated to significant improvements in exercise tolerance.

The practice of calorie restriction, intermittent fasting, and related strategies such the fasting mimicking diet are thought to produce benefits largely through increased or more efficient operation of the cellular maintenance process of autophagy. The various forms of autophagy work to remove damaged molecules and structures in the cell, and better cell function maintained over time throughout the body is expected to result in slowed aging. Certainly a great many of the approaches shown to slow aging in short-lived species are characterized by improved autophagy, and influence the same regulatory systems that are triggered by a low calorie intake and consequent hunger.

Autophagy is a prosurvival mechanism for the clearance of accumulated abnormal proteins, damaged organelles, and excessive lipids within mammalian cells. A growing body of data indicates that autophagy is reduced in aging cells. This reduction leads to various diseases, such as myocardial hypertrophy, infarction, and atherosclerosis. Recent studies in animal models of an aging heart showed that fasting-induced autophagy improved cardiac function and longevity. This improvement is related to autophagic clearance of damaged cellular components via either bulk or selective autophagy (such as mitophagy).

Short-term caloric restriction (CR) for 10 weeks in mice rejuvenated symptoms of the aging heart, such as significant improvement in diastolic function and regression of age-dependent cardiac hypertrophy. Moreover, CR reversed age-dependent cardiac proteome remodeling and mitigated oxidative damage and ubiquitination in these mice. In aged animals, hypertrophy, and fibrosis, as well as systolic and diastolic dysfunctions, improved after CR. The beneficial effects of CR observed in cardiomyocytes include enhanced mitochondrial fitness and reduced oxidative stress, apoptotic cell death, inflammation, and importantly, senescence.

In vasculature, CR helps improve endothelial cell function and attenuates collagen deposition, elastin remodeling, and oxidative stress; as a result, CR reduces arterial stiffness. Another study revealed improvements in numerous markers of cardiovascular health in humans after short-term periodic fasting, which is also a pro-autophagic dietary regimen.

In conclusion, fasting-induced autophagy is beneficial for ensuring cardiac function, preventing disease, and improving longevity. However, additional studies in vivo in animal models of cardiac aging are needed to determine the specific molecular mechanisms involved in normalizing autophagy by fasting. In addition, large-scale studies on humans are needed. Importantly, further in vitro research should be directed toward human cardiac tissues to better understand the molecular mechanisms of fasting-induced autophagy and its beneficial effects on longevity pathways and prevention of cardiovascular disease.

Link: https://doi.org/10.4330/wjc.v16.i3.109

Researchers here explore age-related changes that take place in the innate immune cells known as macrophages, as well as the precursor circulating cell type known as monocytes. Macrophages undertake a wide range of tasks, not just responsible for chasing down infectious pathogens, but also clearing molecular waste and cell debris, destroying problematic cells, and helping to coordinate regenerative processes following injury. Altered macrophage behavior is implicated in a range of age-related diseases, and this is also the case for changes that take place in the analogous cell population of microglia resident in the central nervous system. A better understanding of these alterations may lead to ways to restore a more youthful pattern of behavior in these cells.

Macrophages are central innate immune cells whose function declines with age. The molecular mechanisms underlying age-related changes remain poorly understood, particularly in human macrophages. We report a substantial reduction in phagocytosis, migration, and chemotaxis in human monocyte-derived macrophages (MDMs) from older (more than 50 years old) compared with younger (18-30 years old) donors, alongside downregulation of transcription factors MYC and USF1.

In MDMs from young donors, knockdown of MYC or USF1 decreases phagocytosis and chemotaxis and alters the expression of associated genes, alongside adhesion and extracellular matrix remodeling. A concordant dysregulation of MYC and USF1 target genes is also seen in MDMs from older donors. Furthermore, older age and loss of either MYC or USF1 in MDMs leads to an increased cell size, altered morphology, and reduced actin content. Together, these results define MYC and USF1 as key drivers of MDM age-related functional decline and identify downstream targets to improve macrophage function in aging.

Link: https://doi.org/10.1016/j.celrep.2024.114073

This messy popular science article is an essay length expression of futility on the part of a journalist who accepts that he is not equipped to understand the field of aging research and the longevity industry that has arisen in the past decade. One can talk to the talking heads, but they will all say something different. One can look for proof of efficacy for specific approaches, and find only contradictory data, or only compelling animal data, or only small effect sizes, and a lack of the sort of certainty that arises from large human trials. Those trials are still in the future for near every approach to the treatment of aging that might work.

Like most tours of the field written by journalists, the article lumps together terrible approaches, promising approaches, approaches with good supporting data, approaches with mixed to bad supporting data, and makes little attempt to distinguish between them. The journalist cannot distinguish between them, he doesn't have the several years of learning the science that would be needed to even start to have a useful opinion on approach A versus approach B. For the layman it is just a list, and those most willing to talk about the list are those with a vested interest in profiting from companies working on one item or another item, or are scientist with career prospects that require them to be overly cautious in their public pronouncements. Objectivity is hard to find.

The Wild Science of Growing Younger

There are a lot of hyperbolic and crazy-sounding theories and assertions in the vast movement to counteract the inexorable march from the quick to the dead. Xprize founder Dr. Peter Diamandis thinks we may one day upload our consciousness to the cloud. As such, the 62-year-old is doing everything he can to keep his body healthy in the meantime and maybe reach "longevity escape velocity" - continuing to extend his life long enough to take advantage of ever-more life-extending methods. His business partner - motivational speaker and entrepreneur Tony Robbins - says that stem cell injections he received in Panama (because it's illegal in the U.S.) not only repaired a torn rotator cuff but rejuvenated his entire body. Half-billionaire Bryan Johnson reportedly spends about two million dollars a year on testing, taking more than 100 drugs and supplements, and - for a time - infusing his teenage son's blood plasma. And they are not alone. Jeff Bezos, Yuri Milner, and other tech titans are reported to have together poured about $3 billion into Altos Labs, a startup promising to reprogram human cells to their youthful state.

Rejuvenation efforts also promise to brighten the twilight years by allowing people to live longer and be healthier and more vigorous. Picture 80-year-olds with the body of a 60-year-old. Proponents talk about not only extending lifespan but also what they call healthspan. "It's this biology of aging that makes us get Alzheimer's or cancer or heart disease or diabetes," says Dr. Nir Barzilai. "Aging is the mother of those diseases ... You deal with the mother, and you don't have those kids." After speaking with a dozen experts or advocates, reading four books, parsing over 30 research papers, and absorbing popular press coverage, I know two things about the possibility of slowing or reversing aging. First, anyone can do a few cheap, simple things (like exercise) to improve their longevity prospects. Second, several new tactics, technologies, and tools might someday work.

If you'd hoped for a conclusive destination at the end of this journey, I'm sorry. But in place of answers, we have a framework for evaluating the many questions that emerge. Science has a good sense of what healthy aging should look like. And objective research can begin to explore if any far-fetched ideas mimic that, without bad side effects. Some medications might slow down some aspects of aging. Or perhaps the side effects of these meds just substitute new health problems for the ones proponents aim to fix. You might wait for more info on that before you swallow. Can we inject foreign cells to repair our bodies or inject chemicals that reinvigorate our own cells? This seems to work in mice, worms, or petri dishes. But people without vested interests say we need much more evidence. That's going to take a long time. For so much of anti-aging or reverse-aging science, the old academic refrain applies: "further research is needed."

The evidence for transfusion of young plasma to produce benefits in old animals and human patients is mixed. Despite compelling demonstrations for the dilution of blood to produce benefits in older individuals, there remain many research groups who consider that the primary goal should be the identification of factors within young blood that can produce improvements to health. Inconveniently for those who argue for the primacy of dilution in producing the benefits of plasma transfusion, there are studies such as this one in which factors derived from young plasma do in fact improve health significantly in old mice.

Recent investigations into heterochronic parabiosis have unveiled robust rejuvenating effects of young blood on aged tissues. However, the specific rejuvenating mechanisms remain incompletely elucidated. Here we demonstrate that small extracellular vesicles (sEVs) from the plasma of young mice counteract pre-existing aging at molecular, mitochondrial, cellular and physiological levels. Intravenous injection of young sEVs into aged mice extends their lifespan, mitigates senescent phenotypes, and ameliorates age-associated functional declines in multiple tissues.

Quantitative proteomic analyses identified substantial alterations in the proteomes of aged tissues after young sEV treatment, and these changes are closely associated with metabolic processes. Mechanistic investigations reveal that young sEVs stimulate PGC-1α expression in vitro and in vivo through their microRNA cargoes, thereby improving mitochondrial functions and mitigating mitochondrial deficits in aged tissues. Overall, this study demonstrates that young sEVs reverse degenerative changes and age-related dysfunction, at least in part, by stimulating PGC-1α expression and enhancing mitochondrial energy metabolism.

Link: https://doi.org/10.1038/s43587-024-00612-4

You might compare the LEV Foundation's Rodent Aging Interventions Database with the DrugAge database, both emerging from the efforts of researchers who found themselves frequently reviewing the existing literature on age-slowing interventions in animal models. One of the things to bear in mind about the existing literature is that rodent studies that show an apparent modest slowing of aging frequently fail to replicate when later investors take a more rigorous approach, with larger numbers of mice. The history of the NIA Interventions Testing Program is largely a repeated demonstration of this point.

The Rodent Aging Interventions Database (RAID) project arose as a result of work conducted during late 2022 in preparation for the first study in LEV Foundation's Robust Mouse Rejuvenation (RMR) program: specifically, a comprehensive survey conducted by LEVF of publications documenting successful lifespan extension in strains of rodents (mice and rats) with normal baseline lifespans. That survey played an important role in informing the selection of interventions for the RMR program.

Recognising that this compilation of data may be of interest to other researchers in the field of longevity/aging research, we decided to make it publicly available. To enable convenient exploration of the results, we have also developed a visualization tool which depicts the increases in lifespan achieved in different studies as a single bar chart.

The dataset queried by this tool is intended to cover all published studies that meet the inclusion criteria: (a) in mice (Mus musculus) or rats (Rattus norvegicus), (b) a genetic background consistent with normal aging rates (e.g. no progeria, PolG mitochondrial DNA mutator, Alzheimer's models such as APP/PS1, etc.), and (c) the study reports an intervention with some statistically significant effect on average or maximum lifespan. It is our intention to update the dataset periodically, but some newer (or recently identified) publications may not yet be indexed.

Link: https://www.levf.org/projects/raid