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03 April 2026 - 11:18 AM
Oxidized LDL in Vascular Dementia 02 April 2026 - 06:03 PM
Low density lipoprotein (LDL) particles are a class of cholesterol transporter, carrying cholesterol out from the liver where it is manufactured to the rest of the body via the bloodstream. LDL and its cargo can become oxidized as a result of interactions with the variety of oxidizing molecules produced in the normal operation of metabolism. This oxidized LDL is toxic and places stress upon cells in the blood vessel walls that encounter it. The level of oxidation increases globally with age, one of the known issues in an aged metabolism, and as a consequence there are more oxidized LDL particles and oxidized cholesterol molecules to cause problems in the vasculature. The research community is largely focused the role of oxidized LDL and oxidized cholesterol in the onset and progression of atherosclerosis, meaning the damage done to vascular endothelium that leads to excess accumulations of cholesterol, dysfunction in the macrophage cells drawn to attempt a repair, and the growth of an atherosclerotic plaque. There are other downstream consequences, however.
In today's open access review, researchers largely skate over the topic of atherosclerosis to discuss how oxidized LDL particles can contribute to vascular dementia. This is a matter of inflammation, endothelial dysfunction, and blood-brain barrier compromise in the microvasculature of the brain, issues distinct from the atherosclerotic plaque that forms in large arteries. At the high level, we might envisage the vasculature in the brain as a transformer that converts the biochemical issue of too many oxidizing molecules into chronic inflammation and related dysfunctions in brain tissues. Oxidative stress, mitochondrial dysfunction, and unresolved inflammatory signaling all circle round one another in aging, feeding into one another and downstream issues. It remains to be seen as to what the best points of intervention are, but clearing senescent cells and fixing mitochondrial dysfunction seem the best starting points at the present time.
Converging evidence indicates that the interplay of aging, LDL, and especially oxidized LDL (oxLDL) is a critical driver of cerebrovascular injury underlying vascular cognitive impairment and dementia (VCID). Epidemiological studies have demonstrated that midlife hypercholesterolemia is associated with an increased risk of dementia, with each ∼1 mmol/L rise in LDL levels linked to an estimated 8% higher incidence of all-cause dementia. Mechanistically, atherosclerosis-prone conditions like high LDL promote intracranial arterial disease that compromises cerebral perfusion and precipitates ischemic injury. Beyond large vessels, cholesterol and its oxidized derivatives can accumulate in the cerebral microvasculature, inciting local inflammation and neurodegeneration.
In the aging brain, these processes are compounded by an intrinsically fragile vasculature, establishing a strong case that aging, LDL, and oxLDL must be studied synergistically in the context of brain microvascular health and VCID pathogenesis. OxLDL emerges as a particularly deleterious player within the neurovascular unit (NVU). Once native LDL particles undergo oxidation, they trigger endothelial dysfunction more potently than native LDL. OxLDL engages endothelial cells to upregulate adhesion molecules and pro-inflammatory pathways, while directly degrading the integrity of the endothelial barrier. This damage to the blood-brain barrier (BBB) permits leakage of neurotoxic blood-derived factors into the brain parenchyma, exacerbating oxidative stress and inflammation within brain tissue.
Indeed, oxLDL creates a vicious cycle: it is readily taken up by macrophages and brain glia, generating foam cells and further reactive oxygen species (ROS) and cytokine release. The result is chronic neurovascular inflammation, reduced nitric oxide bioavailability (impairing vasodilation), and breakdown of microvascular structure, changes that manifest as small vessel disease, microhemorrhages, and ultimately cognitive impairment. Thus, aging-related oxidative stress and oxLDL together destabilize the BBB and cerebral perfusion, linking peripheral dyslipidemia to the hallmark microvascular lesions of VCID.
View the full article at FightAging
How an Enzyme’s Depletion Makes Fat Worse 02 April 2026 - 04:13 PM
In Aging Cell, researchers have described how the enzyme Pck1, a core part of metabolic activity, is required for staving off senescence in fat (adipose) cells.
The aging of fat
With the decrease in metabolic activity that frequently occurs with aging, human beings often accumulate fat. This fat, itself, also ages; this paper describes it as “one of the most vulnerable tissues”, noting its association with physical problems [1] and its link to metabolic disorders, including insulin resistance [2]. Previous research has found that, in mice, clearing out senescent adipose cells mitigates some of these problems [3].
These researchers have done previous work demonstrating that phosphoenolpyruvate carboxykinase 1 (Pck1) deficiency shortens the lifespan of yeast [4]. As this enzyme is required for proper metabolic function in adipose tissue, the researchers sought to determine its relationship to senescence and aging in this context.
Necessary for mouse health
Unsurprisingly, as in many other tissues, 24-month-old mice were found to have more senescent fat cells (adipocytes) than 4-month-old mice. While overall Pck1 expression was largely restricted to mature adipocytes, the senescent cells expressed considerably less of it. Feeding mice a high-fat diet also decreased Pck1 expression.
The researchers then investigated the role of this enzyme by creating a strain of mice that does not express Pck1 in adipocytes. Compared to wild-type controls, these mice exhibited substantial increases in adipocyte senescence and metabolic issues, such as insulin resistance, at 12 and 24 months of age, with young mice being less affected; this was in spite of the mice not having any significant differences in body weight. A high-fat diet had even more negative effects on these modified mice than it had on wild-type mice.
The adipocytes of these modified mice were found to secrete substantially more SASP factors than those of unmodified mice, particularly at middle age. There was an increase of fibrosis as well along with more signs of immune cell infiltration, demonstrating increased inflammatory effects. Therefore, the researchers surmised that a lack of Pck1 in these cells exacerbates inflammaging, the age-related chronic inflammation that occurs even in the absence of pathogens.
Mitochondrial dysfunction and metabolic effects
Pck1 depletion led to a substantial increase in mitochondrial dysfunction. The affected cells had smaller and more misshapen mitochondria than unaffected cells. The mitochondria were also depolarized, showing a lack of functional ability, and they were afflicted by a rise in reactive oxygen species (ROS). A gene expression analysis found significant downregulations in key proteins needed for proper mitochondrial respiration.
This work identified four metabolites that accumulate in Pck1-depleted adipocytes: fumarate, succinate, glutamate, and DL-glutamate. All four are part of the TCA cycle, which is fundamental to cellular metabolism. Adding additional fumarate to these cells increased their expression of the senescence markers p21 and p16 even further. Further work targeting fumarate found that it was the key metabolite in these problems: removing it mitigated ROS and reduced the expression of the inflammatory cGAS/STING pathway, which had driven these cells senescent.
The researchers note that they do not know why Pck1 decreases in adipocytes with age, stating that this is a topic that they plan to investigate in further research. Similarly, they have not confirmed whether or not Pck1 is specific to adipocytes or if it applies to other tissues as well; they intend to use multi-organ models in order to discover this. However, they note that Pck1 is a “novel therapeutic target” and believe that targeting it may lead to effective treatments in the future.
Literature
[1] Ou, M. Y., Zhang, H., Tan, P. C., Zhou, S. B., & Li, Q. F. (2022). Adipose tissue aging: mechanisms and therapeutic implications. Cell death & disease, 13(4), 300.
[2] Reyes-Farias, M., Fos-Domenech, J., Serra, D., Herrero, L., & Sanchez-Infantes, D. (2021). White adipose tissue dysfunction in obesity and aging. Biochemical pharmacology, 192, 114723.
[3] de Oliveira Silva, T., Lunardon, G., Lino, C. A., de Almeida Silva, A., Zhang, S., Irigoyen, M. C. C., … & Diniz, G. P. (2025). Senescent cell depletion alleviates obesity-related metabolic and cardiac disorders. Molecular Metabolism, 91, 102065.
[4] Yuan, Y., Lin, J. Y., Cui, H. J., Zhao, W., Zheng, H. L., Jiang, Z. W., … & Liu, X. G. (2020). PCK1 deficiency shortens the replicative lifespan of Saccharomyces cerevisiae through upregulation of PFK1. BioMed Research International, 2020(1), 3858465.
View the article at lifespan.io
NR0B2 is Protective of Cartilage, But Expression Decreases as Osteoarthritis Progresses 02 April 2026 - 10:22 AM
Cartilage is one of the least regenerative tissues in the body, and thus damage and aging leads to osteoarthritis, disability, and joint pain. There is considerable interest in finding ways to effectively repair or replace cartilage, provoke existing tissue into greater regenerative capacity, or adjust cellular biochemistry to make cartilage more resilient to damage and cell death. Here, researchers report on the manipulation of a regulatory protein in cartilage cells, NR0B2, also known as SHP, that is reduced in expression as osteoarthritis progresses, and appears to be protective. It might prove to be a useful target to slow the progression of cartilage loss and osteoarthritis.
Osteoarthritis (OA), characterised by cartilage destruction, is the most common degenerative joint disease. However, no effective disease-modifying OA therapy is currently available. Herein, we report orphan nuclear receptor small heterodimer partner (SHP, NR0B2) as a novel catabolic regulator of OA pathogenesis. NR0B2 expression was markedly downregulated in cartilage from patients with OA.
Global or chondrocyte-specific Nr0b2 deletion in male mice exacerbated OA-related pain and structural changes following surgical destabilization of the medial meniscus, accompanied by increased matrix metalloproteinase (MMP)-3 and MMP-13 expression in chondrocytes. Conversely, adeno-associated virus-mediated Nr0b2 overexpression in knee joints of male mice protected against accelerated knee OA caused by Nr0b2 deficiency. Mechanistically, NR0B2 inhibited IKKβ kinase activity via IKK complex interaction, downregulating NF-κB signalling.
Our results demonstrate that NR0B2 has a chondroprotective role in OA progression by regulating matrix-degrading enzymes in an IKKβ/NF-κB-dependent manner, and gene therapy targeting Nr0b2 may be a promising therapeutic strategy for OA.
Link: https://doi.org/10.1038/s41467-026-69864-5
View the full article at FightAging
Severe Infection Correlates with Greater Risk of Later Dementia 02 April 2026 - 10:14 AM
A range of evidence suggests that severe infection causes lasting damage that accelerates degenerative aging. That damage includes an increased burden of senescent cells and their inflammatory signaling, and changes to the immune system that reduce capacity and increase chronic inflammation. Here, researchers process epidemiological data to show that weathering a severe infection is associated with an increased risk of later dementia. Neurodegeneration is accelerated by the chronic inflammation of aging, as are most of the common, ultimately fatal age-related diseases. Unresolved, constant inflammatory signaling is disruptive to tissue structure and function.
Severe infections have been linked to an increased risk of dementia, but both conditions often coexist with other illnesses that may confound this association. Using nationwide Finnish health registry data, we examined the role of noninfectious mental and physical illnesses in the association between severe infections and dementia. This register-based study included 62,555 individuals aged 65 or older in Finland in 2016 who were diagnosed with late-onset dementia between 2017 and 2020 and 312,772 dementia-free controls matched for year of birth, sex, and the follow-up period. Analyses were adjusted for education, marital status, employment, and area of residence, with age and sex accounted for through the matched conditional design and analysis.
Applying a 1-year lag period, we identified 29 hospital-treated diseases that occurred 1-21 years before dementia diagnosis in cases (or index date in controls), had a prevalence of ≥ 1% prior to dementia, and were robustly associated with increased dementia risk (confounder-adjusted rate ratio ≥ 1.20). In addition to 2 infectious diseases (cystitis and bacterial infection of an unspecified site), these included 27 mental, behavioural, digestive, endocrine, cardiometabolic, neurological, and eye diseases, as well as injuries. 29,376 (47%) of the dementia cases had at least one of these diseases diagnosed before dementia.
The associations between the two infectious diseases and dementia risk were not attributable to the 27 comorbid dementia-related diseases diagnosed before infections. The adjusted rate ratio for cystitis was 1.22 before and 1.19 after adjustment for comorbidities, while for bacterial infections of an unspecified site, the rate ratios were 1.21 and 1.19, respectively. The findings were comparable across subgroups defined by sex and education, and stronger for cases of early onset dementia.
Link: https://doi.org/10.1371/journal.pmed.1004688
View the full article at FightAging
