Fight Aging! Newsletter, August 16th 2021

Despite significant advances in diagnosis, drug development, and medical treatment, cardiovascular diseases (CVDs) remain a leading cause of death worldwide. Atherosclerosis, the underlying cause of most CVDs, is a chronic disease of the arteries arising from imbalanced lipid metabolism, a maladaptive immune response, and dysregulated redox homeostasis. While the association between altered lipid metabolism and CVDs is well established, recent evidence indicates that dysregulated metabolism of specific amino acids plays an important role in the pathogenesis of atherosclerosis. Among all amino acids, lower circulating glycine is emerging as a common denominator in CVDs and related metabolic comorbidities, including coronary heart disease, myocardial infarction, obesity, type 2 diabetes (T2D), metabolic syndrome, and non-alcoholic fatty liver disease (NAFLD). While numerous studies reported lower circulating glycine in cardiometabolic diseases, the contribution of impaired glycine metabolism to the development of atherosclerosis remains unclear.

Glycine is the simplest, nonessential amino acid and is synthesized primarily in the liver from serine, threonine, alanine, and glyoxylate. Impaired biosynthesis of glycine in atherosclerosis was suggested by evidence of a decreased glycine/serine ratio in plasma from patients with unstable atherosclerotic plaques. Furthermore, transcriptomics of human and mouse livers revealed suppression of genes driving glycine biosynthesis in NAFLD, predominantly alanine-glyoxylate aminotransferase (AGXT). AGXT is expressed primarily in the liver where it catalyzes glycine biosynthesis from alanine and glyoxylate. Functional deficiencies of AGXT lead to accumulation of glyoxylate, which is rapidly converted to oxalate. Whereas limited literature proposed that dysregulated oxalate metabolism is linked to CVDs, the role of this metabolic pathway in the pathogenesis of atherosclerosis has not been studied yet.

In this study, using targeted metabolomics, we identified decreased ratios of glycine to its precursors or related metabolites, serine, threonine, and oxalate, in patients with coronary artery disease (CAD). As found in patients with CAD, the glycine/oxalate ratio was significantly decreased in atherosclerotic Apoe-/- mice that showed suppression of hepatic AGXT. Utilizing genetic and dietary approaches to manipulate oxalate in Apoe-/- mice combined with studies in isolated macrophages, we demonstrate that increased oxalate exposure drives accelerated atherosclerosis in relation with dysregulated redox homeostasis, an increased inflammatory response, and enhanced hypercholesterolemia. The therapeutic potential of targeting dysregulated oxalate metabolism in atherosclerosis was studied using adeno-associated virus (AAV)-mediated overexpression of AGXT in Apoe-/- mice that showed lower oxidative stress, inflammation, and atherosclerosis. Thus, by studying impaired glycine metabolism in patients and mice with atherosclerosis and using mouse models to manipulate oxalate, we identified dysregulated oxalate metabolism via suppressed AGXT as a driver and therapeutic target in atherosclerosis.

All body cells rely on blood vessels (BVs) for the provision of oxygen and other blood-borne substances and, in certain settings, also for the provision of endothelial-derived paracrine factors. Like other organ systems, the vascular system undergoes aging, which leads to progressive functional deterioration. Given the centrality of BVs to organ homeostasis, it has been hypothesized that vascular aging is an upstream, founding factor in organismal aging, but experimental support for this proposition is limited. Vascular aging involves both large and small vessels, with the latter marked by capillary rarefaction, i.e., age-related failure to maintain adequate microvascular density (MVD). A key homeostatic mechanism preventing MVD reduction relies on the angiogenic activity of vascular endothelial growth factor (VEGF), which by virtue of its hypoxic inducibility, constantly acts to replenish lost vessels and match vascular supply to the tissue needs. The reasons that VEGF fails to do so during aging is unknown.

Compromised vascular function is expected to perturb organ homeostasis in ways conducive for the development of age-related frailties and diseases. Accordingly, counteracting critical facets of vascular aging might be a useful approach for their alleviation. The presumption that insufficient vascular supply in aging is underlined by VEGF signaling insufficiency, primarily (but not exclusively) because of its indispensable role in preventing capillary loss, led us to investigate whether securing a young-like level of VEGF signaling might rectify capillary loss and its sequelae. On the premise that deteriorated vascular function is an upstream driver of multiorgan malfunctioning, it is envisioned that its rectification might confer comprehensive geroprotection.

Although VEGF production is not significantly reduced during mouse aging, longitudinal monitoring revealed that VEGF signaling was greatly reduced in multiple key organs. This was associated with increased production of soluble VEGFR1 (sVEGFR1) generated through an age-related shift in alternative splicing of VEGFR1 mRNA and its activity as a VEGF trap. A modest increase of circulatory VEGF using a transgenic VEGF gain-of-function system or adeno-associated virus (AAV)-assisted VEGF transduction maintained a more youthful level of VEGF signaling and provided protection from age-related capillary loss, compromised perfusion, and reduced tissue oxygenation. Aging hallmarks such as mitochondrial dysfunction, compromised metabolic flexibility, endothelial cell senescence, and inflammaging were alleviated in VEGF-treated mice. Conversely, VEGF loss of function in endothelial cells accelerated the development of these adverse age-related phenotypes. VEGF-treated mice lived longer and had an extended health span, as reflected by reduced abdominal fat accumulation, reduced liver steatosis, reduced muscle loss (sarcopenia) associated with better preservation of muscle-generating force, reduced bone loss (osteoporosis), reduced kyphosis, and reduced burden of spontaneous tumors.

Cardiovascular disease (CVD) is the main cause of death worldwide. Atherosclerosis is the underlying pathological basis of CVD. Mitochondrial homeostasis is maintained through the dynamic processes of fusion and fission. Mitochondria are involved in many cellular processes, such as steroid biosynthesis, calcium homeostasis, immune cell activation, redox signaling, apoptosis, and inflammation, among others. Under stress conditions, mitochondrial dynamics, mitochondrial cristae remodeling, and mitochondrial reactive oxygen species (ROS) production increase, mitochondrial membrane potential (MMP) decreases, calcium homeostasis is imbalanced, and mitochondrial permeability transition pore (mPTP) open and release of mitochondrial DNA (mtDNA) are activated.

mtDNA recognized by TLR9 can lead to NF-κB pathway activation and pro-inflammatory factor expression. At the same time, TLR9 can also activate NLRP3 inflammasomes and release interleukin, an event that eventually leads to tissue damage and inflammatory responses. In addition, mitochondrial dysfunction may amplify the activation of NLRP3 through the production of mitochondrial ROS, which together aggravate accumulating mitochondrial damage.

In addition, mtDNA defects or gene mutation can lead to mitochondrial oxidative stress. Mitochondria are highly dynamic organelles that constantly produce adenosine triphosphate (ATP). Events, such as mtDNA mutation, imbalance in calcium homeostasis, accumulation of oxidative stress products, and metabolic dysfunction are hallmarks of mitochondrial damage. When mitochondria are damaged or dysfunctional, energy production is limited and large quantities of ROS are produced. Increased ROS levels induce endothelial dysfunction, vascular inflammation, and accelerated accumulation of oxidized low density lipoprotein (ox-LDL) in the arterial wall, a phenomenon that promotes atherosclerosis.

Finally, obesity, diabetes, hypertension, and aging are risk factors for the progression of CVD, which are closely related to mitochondrial dynamics. Mitochondrial dynamics may represent a new target in the treatment of atherosclerosis. Antioxidants, mitochondrial inhibitors, and various new therapies to correct mitochondrial dysfunction represent a few directions for future research on therapeutic intervention and amelioration of atherosclerosis.

Evidence has begun to emerge indicating that cancer survivors experience accelerated aging. This study examines this phenomenon by evaluating trajectories of functional decline in older adults with a history of a cancer diagnosis relative to those without a history of cancer.

Community dwelling healthy volunteers in the Baltimore Longitudinal Study of Aging were evaluated. Between 2006 and 2019, 1,728 men and women (aged 22-100) underwent clinical evaluation of functional status; 359 reported having a history of cancer. Longitudinal associations between self-reported cancer history and measures of functional decline were examined using generalized estimating equations. Additionally, time-to-event and Cox proportional hazards models were used to examine trajectories of decline. Where appropriate, age-stratified associations were examined, and models were adjusted for sex, body mass index, race, smoking status, education, and number of comorbid conditions.

Among all participants, a history of cancer was associated with 1.42 greater odds of weak grip strength. Among older participants (older than 65 years of age), those with a history of cancer had 1.61 greater odds of slow gait speed and a 0.11 unit lower physical performance score than those with no cancer history. Time-to-event analysis showed that older individuals with a history of cancer experienced steeper decline in grip strength and gait speed than older adults with no history of cancer. In conclusion, cancer survivors, especially older individuals, demonstrate greater odds of and accelerated functional decline, suggesting that cancer and/or its treatment may alter aging trajectories.

Using data from two large, long-running study projects in the Puget Sound region - one that began in the late 1970s measuring air pollution and another on risk factors for dementia that began in 1994 - researchers identified a link between air pollution and dementia. In the study, a small increase in the levels of fine particle pollution (PM2.5 or particulate matter 2.5 micrometers or smaller) averaged over a decade at specific addresses in the Seattle area was associated with a greater risk of dementia for people living at those addresses. "We found that an increase of 1 microgram per cubic meter of exposure corresponded to a 16% greater hazard of all-cause dementia. There was a similar association for Alzheimer's-type dementia."

Air pollution may be associated with elevated dementia risk. Prior research has limitations that may affect reliability, and no studies have evaluated this question in a population-based cohort of men and women in the United States. Using the Adult Changes in Thought (ACT) population-based prospective cohort study in Seattle, we linked spatiotemporal model-based PM2.5 exposures to participant addresses from 1978 to 2018. Dementia diagnoses were made using high-quality, standardized, consensus-based protocols at biennial follow-ups. We conducted multivariable Cox proportional hazards regression to evaluate the association between time-varying, 10-year average PM2.5 exposure and time to event in a model with age as the time axis, stratified by apolipoprotein E (APOE) genotype, and adjusted for sex, education, race, neighborhood median household income, and calendar time.

We report 1,136 cases of incident dementia among 4,166 individuals with nonmissing APOE status. Mean 10-year average PM2.5 was 10.1 μg/m3. Each 1-μg/m3 increase in the moving average of 10-year PM2.5 was associated with a 16% greater hazard of all-cause dementia. Our results strengthen evidence on the neurodegenerative effects of PM2.5.

About 10-15% of tumor cells extend telomeres through the alternative lengthening of telomeres (ALT) mechanism, which is a recombination-dependent replication pathway. It is generally believed that ALT cells are related to the chromatin modification of telomeres. However, the mechanism of ALT needs to be further explored.

Here we found that TRIM28/KAP1 is preferentially located on the telomeres of ALT cells and interacts with telomeric shelterin/telosome complex. Knocking down TRIM28 in ALT cells delayed cell growth, decreased the level of C-circle which is one kind of extrachromosomal circular telomeric DNA, increased the frequency of ALT-associated promyelocytic leukemia bodies (APBs), led to telomere prolongation and increased the telomere sister chromatid exchange in ALT cells. Mechanistically, TRIM28 protects telomere histone methyltransferase SETDB1 from degradation, thus maintaining the H3K9me3 heterochromatin state of telomere DNA.

Our work provides a model that TRIM28 inhibits alternative lengthening of telomere phenotypes by protecting SETDB1 from degradation. In general, our results reveal the mechanism of telomere heterochromatin maintenance and its effect on ALT, and TRIM28 may serve as a target for the treatment of ALT tumor cells.

Aging is associated with an increased risk of frailty, disability, comorbidities, institutionalization, falls, fractures, hospitalization, and mortality. Searching for strategies to delay the degenerative changes associated with aging and frailty is interesting. We treated old animals intravenously with small extracellular vesicles (sEVs) derived from adipose mesenchymal stem cells (ADSCs) of young animals, and we found an improvement of several functional parameters usually altered with aging, such as motor coordination, grip strength, fatigue resistance, fur regeneration, and renal function. Frailty index analysis showed that 40% of old control mice were frail, whereas none of the old ADSCs-sEVs treated mice were. Molecular and structural benefits in muscle and kidney accompanied this functional improvement.

ADSCs-sEVs induced pro-regenerative effects and a decrease in oxidative stress, inflammation, and senescence markers. The metabolome of treated mice changed to a youth-like pattern. Very interestingly, the effect of ADSCs-sEVs seems to be finite, as we observed in a more long-term experiment that the effect on the functionality of old mice was lost two months after treatment with ADSC-sEVs. Finally, we gained some insight into the miRNAs contained in sEVs that might be, at least in part, responsible for the effects observed. We propose that young sEVs treatment can be beneficial against frailty and therefore can promote healthy aging.

Today, some two thirds of all human funerals owe to the processes of aging. Only 3.7 per cent of cancer patients are under thirty-four, and if a cure for all types of cancers were miraculously found, it would add no more than two years to the average human lifespan, because other age-related diseases would still take their toll. But while the term "pandemic" - from the Greek pán ("all") and dēmos ("people") - does not imply infectious disease, our ethics prevent us from applying it to the nearly 100,000 daily deaths caused by aging.

Yet in 2021, we all agree that the effects of aging must be treated. The United States alone spends over 300 billion in taxpayer funds each year on the treatment of patients with Alzheimer's, and the trillions spent on the age-related mortality risk of COVID-19 by this single country, in this single year, make for a painful calculation. But to preventively fund aging research itself goes beyond the reactive purview of both politics and medical systems.

When asked in a 2013 Pew Research Center survey, 56 per cent of Americans replied they would not want to slow their aging and live up to 120. At first glance, their logic is sound: with an unaltered average health-span, to add another forty years to average human lifespan could be catastrophic, for both individuals and governments. By 2035, demographics in the United States will reach a turning point, with more people in the country aged 65 or older than 18 or younger.

At second glance, however, the Pew survey respondents are the same Americans who, if diagnosed with early signs of Alzheimer's, would do all within reach to slow down its progression. In reality, one cannot successfully slow down the processes of aging without also increasing healthspan. And in techno-progressive societies, a larger number of healthy, long-lived individuals are more likely to mend financial structures than to burden them.

We think of aging as the product of this orphic thing called "time", ignoring that species far less resourceful than ours live on for centuries longer, and some (like the American lobster) do not decrease in strength, do not have their metabolism slowed down, and become more rather than less fertile, with the passage of time. Surely, we can do better than to draw a skewed, myopic ethics, which enshrines human life, even as we treat the biological processes of aging like a mystical, tabooed concept, from which life's meaning is to be derived. When some two thirds of human deaths owe to the effects of aging - a number rapidly increasing with advancements in robotics, vaccines, and self-driving cars - it becomes difficult to argue that death and aging must be recognised as divorced processes.

Several studies have suggested the implication of infectious agents in Alzheimer's disease (AD) pathophysiology with herpes simplex virus type 1 (HSV-1) being one of the most investigated candidates. In fact, the implication of HSV-1 could potentially explain the location, chronology, and the type of damage described in AD. First, HSV-1 is a neurotropic virus with a particular tropism for the temporal cortex, as shown by the localization of lesions in HSV-1 encephalitis and postmortem studies highlighting the presence of HSV DNA in the brains of older adults. HSV-1 also has the ability to move from neurons to neurons, which could explain the progression of lesions to other brain areas.

Second, HSV-1, which remains in a latent state throughout life after primary infection, can periodically reactivate during a temporary immune decline. With advancing age, the development of a long-lasting immunosenescence may allow more frequent and/or more intense reactivations of the virus, thereby explaining the progressive and relatively late onset of AD. Finally, HSV-1 could be linked to genetic risk factors of AD, especially APOE4. The existence of such genetic susceptibility factors could explain why, despite a seroprevalence of ~80% in the elderly, some infected individuals remain "healthy carriers", while others develop clinical consequences of the infection.

Our findings suggest an increased risk of AD in subjects infected by HSV. Infected subjects with an anti-HSV IgG level in the highest tercile (possibly reflecting more frequent reactivations over time) had lower hippocampal volume (HV) compared to uninfected subjects. Infected subjects presented also more microstructural alterations of the parahippocampal cingulum and fornix. Our results are also in favor of an interaction between being infected with HSV and APOE4 status regarding advanced markers of the disease (HV and then incidence of AD). Among APOE4 carriers, infected subjects presented lower HVs, although not significant, and had a two times higher risk of developing AD and a three times higher risk if their anti-HSV IgG level was in the highest tercile. Among APOE4 noncarriers, no associations were observed between HSV status and HV or incidence of AD.

Insilico Medicine, a global company specializing in the applications of the next-generation machine learning technologies for drug discovery and development, announced today that its AI-powered drug discovery platform had delivered a preclinical candidate for kidney fibrosis. Chronic kidney disease affects 10 percent of the world's population, and, unfortunately, it has no cures or efficacious drugs on the market. Kidney fibrosis is the common pathogenesis in the progression of chronic kidney disease ("CKD") and is a major unmet medical need. Approximately 850 million people worldwide have kidney disease often being driven by or associated with kidney fibrosis. We are very excited to see that our AI-powered drug discovery engine has managed to uncover novel targets and novel molecules that have demonstrated preclinical efficacy in kidney fibrosis"

Insilico Medicine achieved a great breakthrough in February 2021 when it announced that its AI system identified a novel drug target and novel compound to treat idiopathic pulmonary fibrosis, which is another fibrotic disease affecting patients worldwide with high unmet medical needs. What also made the discovery noteworthy was that this was achieved within 18 months and a 2.6 million budget. Repeating that success, Insilico Medicine leveraged its platforms to develop the target hypothesis for kidney fibrosis and generate compounds with drug-like properties. The compound that markedly inhibited the development of fibrosis and significantly improved myofibroblast activation are critical for tissue repair and wound healing. Insilico Medicine plans to complete the IND-enabling studies for this program in 2022.

The TDP-43 protein is linked to multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 plays many vital roles within cells, but, under certain circumstances, it can clump together to form toxic aggregates that damage cells and prevent TDP-43 from performing its normal functions. TDP-43 aggregates are found in the brains of most ALS patients and ~45% of FTD patients and are also linked to several other neurodegenerative disorders, including some cases of Alzheimer's disease. The aggregates form not only in neurons, but also in other brain cell types such as oligodendrocytes. These latter cells protect neurons and speed up the transmission of nerve impulses by wrapping neurons in a fatty substance called myelin.

Researchers have previously shown that oligodendrocytes need TDP-43 to survive and wrap neurons in myelin. In the new study, researchers find that one reason oligodendrocytes are dysfunctional in the absence of TDP-43 is that they are unable to synthesize or take up the cholesterol they need to sustain myelin production.

Cholesterol is such a major component of myelin that 25% of the body's total cholesterol can be found in the central nervous system. Oligodendrocytes are known to synthesize large amounts of cholesterol for themselves, but they can also acquire it from other brain cells called astrocytes. Researchers determined that, in the absence of TDP-43, oligodendrocytes lack many of the enzymes required to synthesize cholesterol, and also have reduced levels of the low density lipoprotein receptor that can take in cholesterol from outside the cell. Supplementing these TDP-43-deficient cells with cholesterol restored their ability to maintain the myelin sheath.

Similar defects in cholesterol metabolism may occur in patients, where the formation of aggregates might prevent TDP-43 from performing its normal functions. Researchers analyzed brain samples from FTD patients and found that their oligodendrocytes produced lower amounts of two key enzymes required for cholesterol synthesis, while the low density lipoprotein receptor was incorporated into TDP-43 aggregates.

In this study, we aimed to improve biological age algorithms through a population-risk-based framework. Recent work has introduced a novel measure of 'phenotypic age', developed and validated on NHANES III data. A Gompertz proportional hazards regression was applied to account for the hazard of mortality when selecting clinical biomarkers in the training dataset. This approach is unlike most of the previous biological age algorithms, which largely aimed to model chronological age as the dependent variable. As a result, it is able to capture the association between accelerated biological age and elevated risk of age-related comorbidity.

However, the "phenotypic age" algorithm was unable to establish a significant link between accelerated aging and elevated risk for dementia. We hypothesized that this caveat was not due to the population-risk-framework itself, but because the "phenotypic age" was trained in the NHANES data, which has a relatively younger age distribution than is common for neurological outcomes. Furthermore, we investigated whether by including markers of neurodegeneration, we could improve the prediction of neurological outcomes in advanced-aged cohorts.

Our approach to improve the biological age models comprised of two steps. First, we validated the "phenotypic age" algorithm in the Rotterdam Study. Second, we developed and validated new biological age algorithms in the Rotterdam Study using the same Gompertz proportional hazards regression framework plus neurodegenerative markers (neurofilament light chain, total-tau, amyloid beta-40 and amyloid beta-42). Two variants of a phenotypic blood-based algorithm that either excludes (BioAge1) or includes (BioAge2) neurofilament light chain as a neurodegenerative marker were assessed. BioAge1 and BioAge2 predict dementia equally well, as well as lifespan and healthspan. Each one-year increase in BioAge1/2 was associated with 11% elevated risk of mortality and 7% elevated risk of first morbidities.

With investment money flowing freely into start-ups developing senotherapeutics, and companies like Unity Biotechnology already conducting human trials, Aubrey de Grey is bullish about the sector. "The field of targeting senescent cells has completely exploded. And I would say that it's now become the highest profile area across all the hallmarks of aging. But there's definitely a spectrum of degrees of understanding - there are some people that understand the whole thing really well, and some people who don't."

A simplistic view of the field is that senescent cells are bad for us, and, because there are more of them in older people than there are in younger people, they are associated with aging, so we need to reduce them. "I use the term "death-resistant cells", which doesn't have any connotations about what kind of behaviour the cell is engaging in that is somehow undesirable. It just emphasises the fact that the reason these cells are accumulating, is because the body is failing to get them to commit suicide (apoptosis), which is what normally happens with bad cells."

And de Grey believes that there are "a whole bunch" of questions about how we might go about reducing the number of senescent cells in our bodies. "The most simple way, and something I originally didn't really believe would be possible, is to find drugs that are able to selectively make senescent cells unhappy, and cause them to commit suicide. And it turns out one can find those drugs. The field as a whole is barrelling forward with a wide variety of different synthetic drugs that can induce apoptosis selectively in senescent cells, by a variety of different mechanisms. And that's wonderful. However, pharmaceuticals are always going to have some limitations, they're always going to have some degree of non-selectivity, some toxicity to the cells that we don't want them to kill, and some cells that we do want to kill that they will fail to kill. So it still makes sense for us to consider alternative approaches."

With so much work going on, and so many different ways to tackle the challenge of senescence, there are still no Phase 3 trials in this field. But de Grey believes we're not far away. "I think it's close. Unity Biotechnology are still ahead of the field in terms of progress, the trial that failed last year with a Phase 2 trial, but they've got two other trials in Phase 2 for other indications - they're covering a lot of bases. They're well-funded, they're a really good company, they've got everything going for them, and I think we could be talking no more than a couple of years before we get things through the process."

Extracellular vesicles (EVs) possess properties related to the state of the originating cell, circulate in blood, cerebrospinal fluid, and urine, and provide paracrinehttps://en.wikipedia.org/wiki/Paracrine_signalling">paracrine and remote cell-cell communication messengers. This study investigated whether senescence-associated secretory phenotype (SASP) and immune defense factors in EVs of urine could serve as biomarkers in elderly individuals with and without a comorbidity. Urine samples from young adults and elderly individuals with and without Parkinson's disease (PD) were collected and stored. Urine EVs were separated from a drop-through solution and confirmed by verifying CD9, CD63, CD81, and syntenin expression.

The EVs and drop-through solution were subjected to measurement of SASP cytokines and defense factors. Many SASP cytokines and defense factors could be detected in urinary EVs but not urinary solutions. Elderly individuals (older than 60) had significantly higher levels of the SASP-associated factors IL-8, IP-10, GRO, and MCP-1 in EVs. In contrast, some defense factors, IL-4, MDC, and IFNα2 in EVs had significantly lower levels in elderly adults than in young adults (younger than 30). Patients with and without PD exhibited a similar SASP profile in EVs but significantly lower levels of IL-10 in the EVs from patients with PD.

This study used a simple device to separate urinary EVs from solution for comparisons of SASP and defense mediators between young adults and elders with and without PD. Results from this study indicate that aging signature is present in EVs circulating to urine and the signatures include higher inflammatory mediators and lower defense factors in urinary EVs but not solutions, suggesting a simple method to separate urinary EVs from solutions for searching aging mechanistic biomarkers may make prediction of aging and monitoring of senolytic interventions possible.

The evolutionary conservation of genes that enable the young to run faster and respond robustly to "fight or flight" responses makes sense: It helps them to catch prey or evade predators, thereby ensuring their reproductive success. However, some of these genes carry a steep price that animals need to pay when they grow older. Research shows that turning on CaMKII through a chemical reaction caused by adding oxygen, known as oxidation, strengthens these survival responses for young animals. However, oxidative stress increases with aging, which leads to excessive activation of CaMKII. Elevated CaMKII activity has long been linked to tissue damage seen in heart failure, atrial fibrillation, cancer, lung diseases, and neurodegenerative diseases.

Researchers genetically engineered mice so their CaMKII is resistant to oxidation. They then used mouse-sized treadmills to compare the athletic performance of mice with and without CaMKII oxidation. They found that mice with oxidized CaMKII were able to run, on average, about 150 meters further and about 5 meters per minute faster than the mice with oxidation-resistant CaMKII. Further experiments showed that CaMKII activity in the mouse muscle tissue increased the expression of cellular pathways related to inflammation, diabetes, enlarged heart, seizures, and obesity.

Researchers then used a gene-cutting and insertion tool called CRISPR to add the oxidation site characteristic of mammalian CaMKII to the CaMKII gene in fruit fly DNA, normally lacking that site. In one experiment, the flies were placed into glass tubes and allowed to climb to the top of the tube. The researchers found that flies genetically modified to have the oxidizable CaMKII climbed higher and 5mm per second faster than flies with the oxidation-resistant CaMKII. Despite having better physical performance and cardiac function, the genetically modified flies experienced a more rapid age-related decline and they died at a younger age. The hearts of the genetically modified flies are more vulnerable to damaging effects of excessive oxidants.