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13 January 2026 - 02:23 AM
Arguing for Sirtuins to be Involved in Known Interventions to Modestly Slow Vascular Calcification 12 January 2026 - 07:09 PM
Calcification of tissues involves the inappropriate deposition of calcium structures. It is a feature of aging in the cardiovascular system particularly, where calcification contributes to stiffening and dysfunction of tissues. Calcification proceeds alongside the development of atherosclerotic plaque, and thus has long been used as a marker to assess the extent of atherosclerotic cardiovascular disease, but it is a distinct mechanism and pathology. Two people with the same degree of vascular thickening and plaque development can have quite different degrees of calcification.
At the present time there is little that can be done about calcification of blood vessel walls and structures of the heart. As for many aspects of aging, there is evidence for some approaches to be able to modestly slow the progression of calcification, but means of robust and sizable reversal of calcification have yet to be developed. The best widely available approach achieved to date is EDTA chelation therapy, and this is nowhere near as effective or reliable as one might hope it to be.
In today's open access paper, researchers discuss the role of sirtuins in the mechanisms thought to be involved in modest slowing of vascular calcification. The primary point of focus is the long-standing antidiabetic drug metformin, and thus much of the data is derived from diabetic patients and mice. The likely effect sizes are small, and may be more relevant to a diabetic aging metabolism than to a normal aging metabolism. All in all, this is of more academic interest to those following the ongoing story of research into sirtuins than it is of relevance to efforts to treat aging as a medical condition.
Mechanism and treatment of Sirtuin family in vascular calcification
The SIRT family has shown potential in alleviating vascular aging by inhibiting inflammation, reducing endoplasmic reticulum stress, lowering mitochondrial oxidative stress, and promoting DNA damage repair, all of which contribute to the suppression of vascular calcification. Notably, SIRT1, SIRT2, SIRT3, SIRT6, and SIRT7 have demonstrated therapeutic potential in the treatment of vascular calcification (VC). The occurrence of VC involves the participation of multiple factors, primarily attributed to the abnormal deposition of calcium and phosphorus in the vascular wall. This article primarily discusses how the SIRT family can ameliorate VC through various.
Recently, some studies have confirmed that ferroptosis can promote VC, indicating that metformin may alleviate the development of hyperlipidemia-associated VC by inhibiting ferroptosis. Ferroptosis is a form of cell death characterized by iron-dependent lipid peroxidation, regulated by multiple pathways, including redox balance, lipid metabolism, and energy metabolism. Metformin enhances autophagy and inhibits abnormal cell proliferation through the AMPK/SIRT1-FoxO1 pathway, thereby mitigating oxidative stress in diabetic nephropathy. Previous studies have demonstrated that metformin can increase the expression of SIRT3 and GPX4, significantly elevate the levels of phosphorylated mTOR and phosphorylated AMPK, and improve polycystic ovary syndrome in mice by inhibiting ovarian ferroptosis.
SIRT proteins may serve as crucial intermediates for metformin's inhibition of ferroptosis-related vascular calcification. They play a synergistic role by regulating the antioxidant system, iron metabolism, and cellular phenotype transformation. Future research should concentrate on specific activation strategies for SIRT proteins, such as selective agonists, to enhance the targeted therapeutic effects of metformin.
Hesperidin has been shown to prevent the development of calcific aortic valve disease via the SIRT7-Nrf2-ARE axis. Future studies could further investigate the SIRT family's pathways that inhibit VC through ferroptosis. Moreover, the SIRT family influences VC through various signaling pathways, including the Wnt/β-catenin, Runx2, NF-κB, and JAK/STAT pathways, as well as the AMPK signaling pathway. Additionally, the role of the SIRT family in VC is noteworthy, with current research primarily focusing on SIRT1, SIRT2, SIRT3, SIRT6, and SIRT7, while the functions of other SIRT proteins in VC remain to be explored. Clinically, it has been observed that a significant number of patients requiring coronary intervention exhibit multiple calcifications in the vessel walls; thus, investigating methods to prevent and delay the progression of VC is a promising area for future research.
View the full article at FightAging
A Protein That Exacerbates Heart Disease With Age 12 January 2026 - 06:05 PM
Researchers publishing in Aging Cell have found that Hevin, a protein found in the extracellular matrix that increases with age, leads to heart problems in older male mice.
Inflammaging contributes to heart disease
The researchers begin by outlining the mechanisms involved in inflammaging, noting how it is closely connected to various progressive problems in the heart, leading to its gradual loss of function [1, 2]. Unsurprisingly, suppressing inflammatory cytokines led to better cardiac outcomes in mice [3], and prolonging lifespan by preventing inflammaging-related heart disease has been a biotechnology goal for some time.
Macrophage behavior is a key part of this relationship. Pro-inflammatory M1-polarized macrophages are good at killing off pathogens, but they cause damage to surrounding tissues; M2-polarized macrophages reverse this process and repair tissues. Aging drives a shift from M2 to M1 behavior [4], and one of the main chemical culprits is CCL5, a ligand that impedes the polarization of macrophages towards M2 [5].
Hevin, which is found in the extracellular matrix, plays a variety of roles in disease. We have previously reported that Hevin has significant benefits against brain aging in mice, but other work has found entirely different functions, including activity against cancer by recruiting macrophages [6]; however, the recruitment is of M1 macrophages, potentially worsening diseases such as pneumonia [7] and non-alcoholic fatty liver disease [8].
Hevin is hell for older animals
Unsurprisingly, Hevin in the plasma increases with age in people, particularly in people over 60 [9]. In line with previous work finding it to be a biomarker of heart failure [10], these researchers found that it is associated with a decrease in ejection fraction.
In mice, Hevin expression does not increase in the heart; rather, it increases in fatty tissues and is then distributed throughout the body, and this increase in Hevin distribution is accompanied by a decrease in the heart’s ability to effectively pump blood. Directly introducing Hevin to 20-month-old mice did not change blood pressure nor heart rate, but it promoted cellular senescence and shortened telomeres in the heart, increased macrophage infiltration along with inflammatory cytokines in cardiac tissue, and increased fibrosis and hypertrophy while contributing to the heart weakening already seen in older mice. However, these negative effects were only seen in older animals; injecting 8-month-old mice with Hevin caused none of these problems.
The researchers then used an adeno-associated virus (AAV) to knock down Hevin. Just like with introducing Hevin itself, this treatment had no effects on younger animals; however, in the 20-month-old mice, many age-related diseases were ameliorated by this treatment. Senescent cell biomarkers decreased, telomeres were lengthened, hypertrophy was diminished, and both hypertrophy and fibrosis were significantly decreased.
Inflammation plays a key role
These effects were found to be largely due to Hevin’s effects on CCL5 in particular, as it significantly promotes the expression of this ligand and CCL5 was indeed found to promote M1 macrophage polarization in the heart. Older mice that were also treated with an anti-CCL5 antibody were partially spared from the inflammatory effects of Hevin injection, and this antibody also partially reversed the associated hypertrophy and fibrosis. Blocking toll-like receptor 4 (TLR4) and its associated p65 pathway had similar effects.
This study had certain limitations. While Hevin expression has sex-related differences in people, only male mice were used in this study, and further work will have to discover its effects on females. While the researchers surmise that Hevin has an amplifying effect on existing age-related processes, precisely why it had no effects on younger animals was not thoroughly investigated.
The connection between Hevin and fat was noted, and the authors suggest that reducing adipose tissue, such as through semaglutide, may be effective against its age-related increase. This, however, remains an open question as well. As Hevin is known to have beneficial effects in other contexts, whether or not it is wise to target it directly or indirectly is still a topic that requires more detailed investigation.
Literature
[1] Liberale, L., Badimon, L., Montecucco, F., Lüscher, T. F., Libby, P., & Camici, G. G. (2022). Inflammation, aging, and cardiovascular disease: JACC review topic of the week. Journal of the American College of Cardiology, 79(8), 837-847.
[2] Liberale, L., Montecucco, F., Tardif, J. C., Libby, P., & Camici, G. G. (2020). Inflamm-ageing: the role of inflammation in age-dependent cardiovascular disease. European heart journal, 41(31), 2974-2982.
[3] Hu, C., Zhang, X., Hu, M., Teng, T., Yuan, Y. P., Song, P., … & Tang, Q. Z. (2022). Fibronectin type III domain‐containing 5 improves aging‐related cardiac dysfunction in mice. Aging Cell, 21(3), e13556.
[4] Becker, L., Nguyen, L., Gill, J., Kulkarni, S., Pasricha, P. J., & Habtezion, A. (2018). Age-dependent shift in macrophage polarisation causes inflammation-mediated degeneration of enteric nervous system. Gut, 67(5), 827-836.
[5] Li, M., Sun, X., Zhao, J., Xia, L., Li, J., Xu, M., … & Xia, Q. (2020). CCL5 deficiency promotes liver repair by improving inflammation resolution and liver regeneration through M2 macrophage polarization. Cellular & molecular immunology, 17(7), 753-764.
[6 Zhao, S. J., Jiang, Y. Q., Xu, N. W., Li, Q., Zhang, Q., Wang, S. Y., … & Zhang, Z. G. (2018). SPARCL1 suppresses osteosarcoma metastasis and recruits macrophages by activation of canonical WNT/β-catenin signaling through stabilization of the WNT–receptor complex. Oncogene, 37(8), 1049-1061.
[7] Zhao, G., Gentile, M. E., Xue, L., Cosgriff, C. V., Weiner, A. I., Adams-Tzivelekidis, S., … & Vaughan, A. E. (2024). Vascular endothelial-derived SPARCL1 exacerbates viral pneumonia through pro-inflammatory macrophage activation. Nature Communications, 15(1), 4235.
[8] Liu, B., Xiang, L., Ji, J., Liu, W., Chen, Y., Xia, M., … & Lu, Y. (2021). Sparcl1 promotes nonalcoholic steatohepatitis progression in mice through upregulation of CCL2. The Journal of clinical investigation, 131(20).
[9] Lehallier, B., Gate, D., Schaum, N., Nanasi, T., Lee, S. E., Yousef, H., … & Wyss-Coray, T. (2019). Undulating changes in human plasma proteome profiles across the lifespan. Nature medicine, 25(12), 1843-1850.
[10] Di Salvo, T. G., Yang, K. C., Brittain, E., Absi, T., Maltais, S., & Hemnes, A. (2015). Right ventricular myocardial biomarkers in human heart failure. Journal of cardiac failure, 21(5), 398-411.
View the article at lifespan.io
A Short History of the Passage of Anti-Aging Medicine from Fantasy to Scientific Development 12 January 2026 - 11:22 AM
Longevity has always been a matter of interest, but absent an earnest scientific endeavor focused on intervention in aging it remained in the realm of fantasy, fraud, and futile wishes. That scientific endeavor was late in arriving, this delay largely the result of a cultural battle spanning the late 20th century that took place between the founders of modern anti-aging clinical practices and supplement industry companies on the one side versus the aging research community on the other. Only over the last thirty years has a scientific community finally emerged to earnestly and openly focus on treating aging as a medical condition.
The pursuit of youth and longevity has accompanied human societies for millennia, evolving from mythological and esoteric traditions toward a scientific understanding of aging. Early concepts such as Greek ambrosia, Taoist elixirs, and medieval "aqua vitae" reflected symbolic or spiritual interpretations. A major conceptual transition occurred between the late nineteenth and early twentieth centuries, when aging began to be framed as a biological process. Pioneering ideas by Metchnikoff, together with early and sometimes controversial attempts such as Voronoff's grafting experiments, marked the first efforts to rationalize aging scientifically. In the mid-twentieth century, discoveries including the Hayflick limit, telomere biology, oxidative stress, and mitochondrial dysfunction established gerontology as an experimental discipline.
Contemporary geroscience integrates these insights into a coherent framework linking cellular pathways to chronic disease risk. Central roles are played by nutrient-sensing networks such as mTOR, AMPK, and sirtuins, together with mitochondrial regulation, proteostasis, and cellular senescence. Interventions, including caloric restriction, fasting-mimicking diets, rapalogues, sirtuin activators, metformin, NAD+ boosters, senolytics, and antioxidant combinations such as GlyNAC, show consistent benefits across multiple model organisms, with early human trials reporting improvements in immune function, mitochondrial activity, and biomarkers of aging. Recent advances extend to epigenetic clocks, multi-omic profiling, gender-specific responses, and emerging regenerative and gene-based approaches. Overall, the evolution from historical elixirs to molecular geroscience highlights a shift toward targeting aging itself as a modifiable biological process and outlines a growing translational landscape aimed at extending healthspan and reducing age-related morbidity.
Link: https://doi.org/10.3390/molecules30244728
View the full article at FightAging
An Opinionated View of Current Issues with Aging Clocks 12 January 2026 - 11:01 AM
Aging clocks are a way to obtain a measure of the state of biological age, the burden of damage and dysfunction that causes age-related disease and mortality. A wide variety of clocks have been developed, but this technology has yet to realize its full promise, which is to be used as a standardized measure of the efficacy of potential age-slowing and age-reversing therapies. If researchers had a robust, reliable way to immediately assess the quality of a therapy, it would dramatically speed research, and focus progress on the best classes of therapies. We might ask why aging clocks have yet to provide this capacity; the article here looks at this question and what needs to be done in order to realize this goal.
What you want to do is what drives decision-making and sets the goalposts. So let's look at the intended uses for aging clocks: (1) R&D: You want to do experiments to understand biology and/or find new candidate therapies, and avoid waiting for aging and death as your readouts. (2) Consumer health optimization: You want to monitor and probability optimize your health. You'll do measurements at regular intervals, and change your behavior by whether the clock goes up or down. (3) Design and interpret clinical trials: You want to select who goes into your trial, or identify people who respond better or worse to some treatment, purely for your own learning. (4) FDA approval: You want to run a clinical trials and get Accelerated Approval from the FDA based on lowering clock scores, ahead of showing improvements in mortality or disease. (5) Medical care: You want to run tests know whether prescribed medicines and behaviors are working. Wrong results are a big deal, as they could lead to wrong treatments (and, in the US, lawsuits galore).
It's telling that today, aging clocks are frequently used for the first two purposes but approximately never for the last three (where the cost of being wrong is high). Evidently, people in charge of these costly decisions do not think that aging clocks are ready to use. Why is that? The original clocks were strictly correlated to chronological age, which is not a very useful thing to estimate. But later clocks have been trained to predict mortality, frailty, and other important outcomes. So the answer must be that we can't yet trust their predictions.
Bold research has given us a proof of concept that the aging process can be tracked with molecular measurements. We should appreciate that. And we should acknowledge that we won't benefit much from talking about clocks' potential for practical uses until we're able to properly benchmark the required performance metrics. So let's decide on the uses we think are most valuable, and make sure we build the infrastructure to track where we are now and whether we're improving. Funding such a clock assessment program is the highest leverage in longevity. Between accelerating R&D and eventually enabling human trials, good clocks are very much worth pursuing.
Link: https://norngroup.substack.com/p/do-we-have-a-useful-aging-clock
View the full article at FightAging
