Mois : août 2024

In Stem Cell Reports, researchers have described how cell subpopulations and division affect the results of epigenetic clocks.

Good, but never perfect

As these researchers note, epigenetic clocks have had successes in analyzing the impact of things that impact biological age, such as the effects of stress and stress reduction [1] and of progeria [2]. However, such things as differentiation of stem cells are known to change the epigenetic markers used by these clocks [3], raising questions about their reliability.

One way of avoiding this is to use single-cell clocks, but those lack the overall precision of other clocks [4] and have not yet been developed for every cell type. Additionally, some tissues have been found to age more slowly than others [5]. Therefore, these researchers dived more deeply into this subject, attempting to find out how clocks are affected by differentiation, tissue type, and cellular proliferation.

Even similar cells age at different rates

The researchers used three types of clocks to analyze tissues in this study: tissue-specific, pan-tissue for a single species, and two universal clocks that measure age for any mammalian species.

Their first experiment was on muscle tissue derived from mice. The stem cells of muscle tissue were calculated as being less than half of the epigenetic age of differentiated muscle cells, even using a sample taken from a single mouse. The universal clocks also found that stem cells were epigenetically younger, although this effect was far less striking.

Even the type of stem cell has an effect. In bone marrow, hematopoietic stem and progenitor cells (HSPCs), which can differentiate towards multiple fates, were examined alongside progenitors committed to lymph or blood cell (myeloid) fates along with differentiated cells. Curiously, HSPCs trended towards being the most aged of this group, while the lymphoid group trended towards being the least. This difference reached statistical significance in the universal clocks, with lymphoid-fated stem cells being reported as the epigenetically youngest with the other three clustered together.

While previous work has found differences in human intestinal tissue between stem cell-rich crypts and differentiated cell-rich villi [6], these researchers found no difference in their sample. They suggest that this difference may be species-specific or due to sampling issues.

Then, the researchers turned to epithelial tissues: specifically, the esophagus, tongue, skin, and lungs. Skin and tongue cells had largely similar measurements between stem cells and differentiated cells, while esophageal stem cells trended towards being slightly older. However, in lung tissue, the pan-tissue clock reported that differentiated cells were twice as old as the stem cells, and the universal clocks reported ages in the decades, far longer than how long any mouse has ever actually lived.

Dividing cells age much faster

With these results in hand, the researchers then looked at cellular division. Epithelial issues that had more cellular divisions were epigenetically older than cells with fewer divisions. Repeatedly dividing stem cells from the antral gland in the stomach, the researchers found that cells that had divided only once were younger than cells that had divided 10 times and far younger than cells that had divided 19 times, according to both pan-tissue and universal clocks. Similar results were found with stem cells that had been allowed to repeatedly divide.

The researchers then went back to whole tissue and found that these results also applied there. In muscle tissue, cell types that do not divide often (quiescent cells) remained relatively young in older animals, while precursor cells that divide frequently were much older. This was compounded by the fact that the number of such rapidly dividing cells declines with age. In muscle tissue, these cells are rare enough that they are unlikely to affect a whole-tissue clock; however, their effects on blood tissue, despite efforts to account for this fact [7], remain “experimentally unverified” according to these researchers.

These results have led the researchers to hypothesize that accumulated DNA damage, and not just epigenetic alterations, leads to an increase in epigenetic age according to clocks. As previous research has found that at least some of this damage can be repaired [8], this offers an important insight for people developing epigenetic interventions.

Literature

[1] Poganik, J. R., Zhang, B., Baht, G. S., Tyshkovskiy, A., Deik, A., Kerepesi, C., … & Gladyshev, V. N. (2023). Biological age is increased by stress and restored upon recovery. Cell Metabolism, 35(5), 807-820.

[2] Horvath, S., Oshima, J., Martin, G. M., Lu, A. T., Quach, A., Cohen, H., … & Raj, K. (2018). Epigenetic clock for skin and blood cells applied to Hutchinson Gilford Progeria Syndrome and ex vivo studies. Aging (Albany NY), 10(7), 1758.

[3] Bock, C., Beerman, I., Lien, W. H., Smith, Z. D., Gu, H., Boyle, P., … & Meissner, A. (2012). DNA methylation dynamics during in vivo differentiation of blood and skin stem cells. Molecular cell, 47(4), 633-647.

[4] Hernando-Herraez, I., Evano, B., Stubbs, T., Commere, P. H., Jan Bonder, M., Clark, S., … & Reik, W. (2019). Ageing affects DNA methylation drift and transcriptional cell-to-cell variability in mouse muscle stem cells. Nature communications, 10(1), 4361.

[5] Horvath, S., Mah, V., Lu, A. T., Woo, J. S., Choi, O. W., Jasinska, A. J., … & Coles, L. S. (2015). The cerebellum ages slowly according to the epigenetic clock. Aging (Albany NY), 7(5), 294.

[6] Lewis, S. K., Nachun, D., Martin, M. G., Horvath, S., Coppola, G., & Jones, D. L. (2020). DNA methylation analysis validates organoids as a viable model for studying human intestinal aging. Cellular and molecular gastroenterology and hepatology, 9(3), 527-541.

[7] Zhang, Z., Reynolds, S. R., Stolrow, H. G., Chen, J. Q., Christensen, B. C., & Salas, L. A. (2024). Deciphering the role of immune cell composition in epigenetic age acceleration: Insights from cell‐type deconvolution applied to human blood epigenetic clocks. Aging Cell, 23(3), e14071.

[8] Beerman, I., Seita, J., Inlay, M. A., Weissman, I. L., & Rossi, D. J. (2014). Quiescent hematopoietic stem cells accumulate DNA damage during aging that is repaired upon entry into cell cycle. Cell stem cell, 15(1), 37-50.

InsideTracker, the leading personalized health provider, today announced significant findings in a study of its digital health platform (DHP).

The results show that long-term DHP use can improve overall health across several critical biomarkers. Notably, it can improve heart health, reduce inflammation, and help reverse the trend toward type 2 diabetes.

The retrospective analysis looked at more than 20,000 generally healthy adults over roughly 5 years. That makes it one of the largest, longest running studies for this group.

For tracking, InsideTracker looked at subjects’ genetic reports (specifically, polygenic risk scores), blood tests (it focused on 39 biomarkers known to predict age-related disease and overall health), and fitness tracker data (key metrics included VO2max, resting heart rate, and sleep quality). Based on those inputs, InsideTracker recommended specific changes in diet, supplements, exercise, and recovery.

Key findings from the study include:

Immediate biomarker improvement: On average, users improved important health markers like LDL, triglycerides, cortisol, and hsCRP after a single test.
Long-term positive results: Health improvements became more dramatic over time. Subjects who used the platform the longest saw the best results.
Blood-sugar regulation: Study subjects with an HbA1c value of 6.5% or higher (the number associated with diabetes) improved significantly in months. Over time, they were able to reach pre-diabetic levels.
Nutritional improvement: Users experienced significant improvements in blood levels of key nutrients like vitamins D, B12, and iron.
Genetic impact: Users with a higher genetic risk (based on polygenic risk scores) had a harder time optimizing biomarkers, while those with a lower genetic risk saw faster results. This suggests genetic tests are useful for planning individual strategies for health improvement.

This study validates InsideTracker’s 2018 peer-reviewed longitudinal analysis, which found that DHPs can help users optimize key biomarkers. This new study takes that finding further by looking at significantly more subjects over a longer timeframe. It confirms the DHP’s ability to optimize biomarkers, but it also shows a long-term trend toward continual improvement.

“We had two goals with this study,” said Nimisha Schneider, lead author and senior director of science and AI at InsideTracker. “We wanted to understand the long-term impact of integrated health data on individual health outcomes, and we wanted to know whether DHPs are effective in improving health-related biomarkers through personalized recommendations. We now have our answers. We found that data, DHPs, and personalized recommendations can have a significant positive impact on our users’ lives. With these tools, we can prevent common diseases associated with early death.”

The results of this study suggest a paradigm shift in preventive health management, where DHPs can effectively monitor and manage conditions before they progress. This could potentially reduce the worldwide burden of chronic diseases and influence future health policies.

“One of the main challenges in the preventative health space is encouraging users to adopt healthy lifestyle habits and stick to them,” said corresponding author Gil Blander, PhD, founder and chief scientific officer at InsideTracker. “The study provides evidence that a DHP like InsideTracker can provide simple and personalized preventative interventions to improve the health and healthspan of individuals and populations at large, which we believe can inform the public’s daily behaviors and institutional approaches to healthcare.”

InsideTracker’s study marks a significant advancement in health tracking. It demonstrates the positive impact of health data, mobile technology, and AI systems designed to identify opportunities for better health.

“AI can harness the power of data and information in a way that no single expert can,” said Renée Deehan, senior vice president of science & AI. “In our case, we use it to assess peer-reviewed clinical studies that evaluate the relationships between a lifestyle intervention—say, walking more—with health biomarkers like LDL cholesterol. We’re pleased to see that our algorithm’s evidence-based recommendations can improve users’ health long-term.”

This study is a continuation of InsideTracker’s research, which improves in depth and sensitivity as its user base grows. The preprint of the study is now available here and is currently under consideration for peer-reviewed publication.

For more information about the study and InsideTracker’s innovative approach to personalized health management, visit InsideTracker.com.

About InsideTracker

Founded in 2009, InsideTracker is the first healthspan optimization platform to combine blood diagnostics, self-reported lifestyle habits, wearable data, and DNA scores. It was created by experts in the fields of aging, genetics, and biometric data, and it uses peer-reviewed research and cutting-edge AI to create personalized health recommendations for members. Read InsideTracker’s peer-reviewed papers in PLOS One, Current Developments in Nutrition, and Scientific Reports. Follow InsideTracker on Instagram, X, and Facebook.

Contacts

For media inquiries and further information, please contact: insidetracker@jacktaylorpr.com.

In Aging, researchers have described how the changing production of skin cells’ proteins is a core part of their age-related decline.

Understanding why skin cells lose their function

In healthy skin, dermal fibroblasts produce the proteins needed to maintain the extracellular matrix (ECM), the network of collagen and elastin that holds soft tissues together [1]. When skin is damaged, they secrete matrix metalloproteinases (MMPs), which destroy the damaged tissue. They summon macrophages to damaged areas to clear away debris and bring in cells to repair the area [2].

Unsurprisingly, with aging, this process is significantly impeded [3]. Aged skin has deteriorated ECM, which is the direct cause of wrinkles [4]. The destructive factors that young skin cells secrete as part of wound healing are constantly secreted in the aged [5]. Older people also have fewer dermal fibroblasts, and they are less able to migrate [6].

This paper takes a molecular look at the fibroblasts, focusing on what proteins they secrete and determining the role that cellular senescence plays in their deterioration.

Proteins and the cytoskeleton

This study compared skin cells derived from younger (under 35) and older (over 55) donors. While the researchers found nearly a thousand differences in secreted proteins (the secretome), under normal circumstances, only 16 of these secreted proteins were more than doubled or halved between the young and the old. When stimulated with the cytokine TGF-β, only 11 of these proteins met this threshold.

Many of the involved proteins were related to the ECM, senesence, and inflammation, and a particularly large fraction was related to enzymatic function. Some were related to actin, the protein responsible for the cells’ structure (cytoskeleton). The protein ACTC1, one of the six isoforms of actin, was very substantially decreased with age.

The total number of proteins (the proteome) that was different between the young and the old was more than four times as large as the secretome: over four thousand proteins were different, with 63 of them being doubled or halved under normal circumstances and 73 with the application of TGF-β. Like the secretome, many of these proteins were related to actin and to the ECM. Curiously, nearly a full quarter of the proteins found in older fibroblasts were ones for which the researchers did not know the functions, if any.

The researchers focused on four specific actin-related proteins. CFL1 was substantially decreased in older people, and this protein is also related to wound healing: removing CFL1 from younger fibroblasts sharply increases the amount of time it takes for these cells to engage in healing in vitro. CORO1C was multiplied substantially in older cells, and the researchers were unable to conclude a reason why this was the case: the related mRNA was not very different between younger and older cells. The same was found to be true for another actin-related protein, FLNB.

ARPC3 may be a key part of this puzzle. This protein was found to be necessary for fibroblast migration, and the researchers believe that it regulates CFL1 and CORO1C. They further hold that the combination of the three acts “together to regulate the actin cytoskeleton and the cytoskeleton regulation itself.” This protein is secreted less by aging cells.

In total, the researchers believe that the proteins involved in the cytoskeleton of skin cells, and their related ability to move, are a core part of skin aging and the related loss of wound healing ability. They hold that further study of these proteins might be productive in learning to better control skin aging.

Literature

[1] Braverman, I. M., & Fonferko, E. (1982). Studies in cutaneous aging: I. The elastic fiber network. Journal of Investigative Dermatology, 78(5), 434-443.

[2] Brun, C., Demeaux, A., Guaddachi, F., Jean-Louis, F., Oddos, T., Bagot, M., … & Michel, L. (2014). T-plastin expression downstream to the calcineurin/NFAT pathway is involved in keratinocyte migration. PloS one, 9(9), e104700.

[3] Brun, C., Jean‐Louis, F., Oddos, T., Bagot, M., Bensussan, A., & Michel, L. (2016). Phenotypic and functional changes in dermal primary fibroblasts isolated from intrinsically aged human skin. Experimental dermatology, 25(2), 113-119.

[4] Makrantonaki, E., & Zouboulis, C. C. (2008). Skin alterations and diseases in advanced age. Drug Discovery Today: Disease Mechanisms, 5(2), e153-e162.

[5] Lupa, D. M. W., Kalfalah, F., Safferling, K., Boukamp, P., Poschmann, G., Volpi, E., … & Krutmann, J. (2015). Characterization of skin aging–associated secreted proteins (SAASP) produced by dermal fibroblasts isolated from intrinsically aged human skin. Journal of Investigative Dermatology, 135(8), 1954-1968.

[6] Reed, M. J., Ferara, N. S., & Vernon, R. B. (2001). Impaired migration, integrin function, and actin cytoskeletal organization in dermal fibroblasts from a subset of aged human donors. Mechanisms of ageing and development, 122(11), 1203-1220.