LongeCityNews Last Updated: 27 December 2025 - 10:16 AM

If you are old enough, you may recall that the pineal gland received a great deal of quite unscientific attention from the early life extension community, decades ago, overlapping to some degree with its association in lineages of mystical thinking with the third eye. We live in a strange world populated by strange people. Scientifically, the pineal gland is a fairly important part of the endocrine system, and like all organs in the body, its normal function becomes disrupted by age. This has consequences, not all of which are fully mapped or understood. Are those consequences plausibly large enough for greater attention to be given to mechanisms of pineal gland aging specifically? The authors of today's open access paper would argue that this is the case.

This highlights one of the challenges inherent in engaging with aging as a phenomenon. The body is complex, and contains many different complex systems, organs, and tissue types. If the approach taken to aging is to run down the list of body parts one by one, then making meaningful progress in the matter of treating aging as a medical condition is going to take a long time. The alternative of focusing on underlying pathological mechanisms rather than tissues has a similar issue. Even today there are many portions of the body for which little has been said in the context of slowing aging or producing rejuvenation. If one looks at the major avenues of development for rejuvenation therapies, such as senolytics and partial reprogramming, one finds that most of the development end of the field is focused on just a few age-related conditions and a few organs.

That said, at this still relatively early stage in the development of the longevity industry it is unclear as to whether anyone should be concerned about the above points, versus maintaining a laser focus on forging ahead as fast as possible to the first rejuvenation therapies. But it is something to think about.

Pineal gland senescence: an emerging ageing-related pathology?

The pineal gland is a photo-neuroendocrine gland located in the midline of the brain outside the blood-brain barrier. It is part of the epithalamus, is attached to the third ventricle by a short stalk, and can weigh up to 180 grams. Its primary role is to receive information about the light-dark cycle from the environment, which it responds to through the production and secretion of melatonin. When it is light, the suprachiasmatic nucleus (SCN) secretes gamma-amino butyric acid (GABA), which in turn inhibits neurons in the paraventricular nucleus (PVN) of the hypothalamus. In darkness, the SCN secretes glutamate, which activates pathways from parvocellular pre-autonomic neurons of the PVN via the superior cervical ganglion to stimulate melatonin production by the pineal gland in response to noradrenaline.

The pineal gland may undergo ageing-related structural and morphological changes, including calcification, gliosis, cyst formation, and reduced density of β-adrenergic receptors, which are hypothesised to reduce melatonin secretion.

We hypothesise that pineal gland senescence may represent an ageing-related pathology as it describes a decline in function. This causes a reduction in the secretion of melatonin that may contribute to ageing-related sleep disorders as well as other physiological, cognitive, and psychiatric dysfunctions related to disturbances in circadian rhythm and melatonin concentrations. The current paper will describe the pathophysiology of the pineal gland and will discuss whether pineal gland senescence should be considered as a diagnostic entity.

The big advantage of aging clocks based on clinical biomarkers, such as the results of a complete blood count, or LDL cholesterol level, and so forth, is that one can at least theorize a little about what is going on under the hood when the clock output changes to indicate a higher or lower biological age. Each of the underlying biomarkers has meaning and a body of work attached to it, which is not the case for epigenetic clocks and barely the case for proteomic or transcriptomic clocks. Phenotypic age is the prototype of a widely used clinical biomarker clock. Others have been developed in recent years, and here find yet another recently published novel clinical biomarker clock.

Biological aging clocks offer valuable insights into age acceleration and disease development, making them a very powerful clinical tool for preventive medicine. However, the applicability of biological aging clocks in preventive clinical settings is closely linked to the effectiveness and efficiency of biomarker screening protocols, as well as their economic feasibility. To address this, we investigated the relationship between the performance of the regression model and the number of biomarkers utilized. Our aim was to unlock the full preventive potential of our biological aging clock.

We used a clinical cohort dataset from the Bumrungrad International Hospital in Bangkok, Thailand, encompassing 184,833 individuals and comprising 597,781 samples from 2000 to 2022. The total of 597,781 samples contained data on 174 clinical biochemistry biomarkers. Through expert consensus and iterative refinement, the biomarker set was refined to 51. Using an iterative approach, we systematically removed biomarkers with the least impact on predictive performance, ultimately narrowing the model down to six clinical biochemistry markers plus sex. These six biomarkers were creatinine, hemoglobin A1c (HbA1c), alanine aminotransferase (ALT), high-density lipoprotein (HDL), triglycerides, and albumin.

Based on only seven biomarkers, our clock accurately predicts both self-reported and physician-annotated ICD health data, indicating an increased hazard ratio. Importantly, the clock is robust even in the presence of acute infections or transient immune activation. To demonstrate the multi-ethnic generalizability of our biological age clock, we validated our approach using data from both the NHANES and UK Biobank cohorts. Our approach demonstrates the feasibility of a simple, robust, and interpretable clinical aging clock with potential for real-world implementation in personalized health monitoring and preventive care.

Link: https://doi.org/10.1038/s41598-025-27478-9

In recent years a number of different groups have generated aging clocks intended to assess distinct biological ages for different organs and systems in the body, OrganAge being one example. Data from large human populations suggests that different organs and systems can age at somewhat different rates. Here, researchers use UK Biobank data to generate a novel organ specific proteomic clock, producing similar data to the earlier OrganAge research program.

Organ-specific plasma protein signatures identified via proteomics profiling could be used to quantitatively track organ aging. However, the genetic determinants and molecular mechanisms underlying the organ-specific aging process remain poorly characterized. Here we integrated large-scale plasma proteomic and genomic data from 51,936 UK Biobank participants to uncover the genetic architectures underlying aging across 13 organs.

We identified 119 genetic loci associated with organ aging, including 27 shared across multiple organs, and prioritized 554 risk genes involved in organ-relevant biological pathways, such as T cell-mediated immunity in immune aging. Causal inference analyses indicated that accelerated heart and muscle aging increase the risk of heart failure, whereas kidney aging contributes to hypertension. Moreover, smoking initiation was positively linked to the aging of the lung, intestine, kidney, and stomach. These findings establish a genetic foundation for understanding organ-specific aging and provide insights for promoting healthy longevity.

Link: https://doi.org/10.1038/s41467-025-67223-4

As researchers note in today's materials, there is clear an association between periodontal disease and the progression of atherosclerosis. Atherosclerosis is universal in older humans, the growth of fatty lesions in blood vessel walls that ultimately impede circulating blood flow to a fatal degree or rupture to cause stroke and heart attack. The degree of atherosclerosis at a given age is highly variable across the human population, however. The degree to which atherogenic processes in any two individuals are driven by the same stimulus, such as increased LDL cholesterol levels or increased lipoprotein A levels or increased inflammation, can be very different. This makes it somewhat challenging to talk about how much of a problem any given atherogenic issue actually poses.

This is much the case for periodontitis and its contribution to atherosclerosis. One can demonstrate mechanisms that in principle allow periodontitis to make inflammatory diseases worse elsewhere in the body, primarily that bacteria and their inflammatory metabolites can leak into circulation via the injured gums. But it is a step from there to find good correlational data in human studies, let alone data that convincingly puts a number to the degree of risk produced by periodontitis. Still, avoiding chronic inflammation in later life is well established to be a beneficial goal for a wide range of reasons. Chronic inflammation is disruptive to tissue structure and function in many contexts, and wherever reasonable efforts can be taken to reduce sources of inflammation, the results should be worth it.

Gum disease may be linked to plaque buildup in arteries, higher risk of major CVD events

Although periodontal disease and atherosclerotic cardiovascular disease (ASCVD) share common risk factors, emerging data indicates there is an independent association between the two conditions. Potential biological mechanisms linking periodontal disease with poor cardiovascular outcomes include direct pathways such as bacteria in the blood and vascular infections, as well as indirect pathways such as chronic systemic inflammation.

Numerous studies have found that periodontal disease is associated with an increased risk of heart attack, stroke, atrial fibrillation, heart failure, peripheral artery disease, chronic kidney disease, and cardiac death. Although periodontal disease clearly contributes to chronic inflammation that is associated with ASCVD, a cause-and-effect relationship has not been confirmed. There is also no direct evidence that periodontal treatment will help prevent cardiovascular disease. However, treatments that reduce the lifetime exposure to inflammation appear to be beneficial to reducing the risk of developing ASCVD.

Periodontal Disease and Atherosclerotic Cardiovascular Disease: A Scientific Statement From the American Heart Association

Direct mechanisms of the association between periodontal disease and atherosclerotic cardiovascular disease (ASCVD) are thought to be through bacteremia and vascular infection. Dental plaque in periodontal disease contains multiple bacterial strains. Periodontal pockets, with manipulation of the tissue, can result in bleeding, which allows periodontal bacteria to enter systemic circulation. Once in the bloodstream, pathogens can trigger a systemic inflammatory response. This, along with increased vascular permeability, could lead to endothelial dysfunction. Endothelial dysfunction can be a sign of early subclinical atherosclerosis.

Bacteremia from chronic periodontal infections may increase the inflammatory burden that accelerates atherogenesis. Inflammation due to direct oral microbiome actions may affect systemic inflammation of blood vessel walls through two modes: direct invasion of bacteria through the diseased and inflamed periodontal tissues into the general circulation and phagocyte-mediated bacterial translocation. The oral microbiome thereby invades vascular tissues, which may experience acute inflammation, which, in the absence of complete resolution, could lead to chronic inflammation and ASCVD.