Mois : août 2024

A researcher publishing in Biogerontology has reviewed the literature on the relationship between cellular senescence and the immune system, finding that dwindling immune surveillance allows senescent cells to accumulate.

The immune system needs to be deadly

On the cellular level, the bodies of vertebrates are brutal police states. Immune cells report, attack, and kill anything that gives off improper chemical signals, which includes the body’s own cells. When immune cells go after healthy, functioning cells, this is a potentially fatal immune disorder; however, when they are convinced not to attack unhealthy cells, such as in tumors, this can lead to the spread of cancer.

Senescent cells are also frequently policed and destroyed by the immune system. However, with aging, this ability declines, which is part of why senescent cells accumulate in older people [1]. While senescent cells and their SASP are often associated with inflammation, there is an increase in anti-inflammatory activity as well; for example, senescent cells in mice have been found to greatly suppress immune activity in a way that leads to the development of cancer [2].

Much of this anti-immune activity originates from immunosuppressive cells, such as Tregs, myeloid-derived suppressor cells (MDSCs), and healing-polarized M2 macrophages. Polarizing macrophages away from the M1 inflammatory type and towards healing is normally considered a good thing in the context of systemic inflammation in aging (inflammaging), but systemic immunosuppression has been reported to make inflammaging worse [1].

Senescent cells, themselves, also secrete compounds that convince immune cells not to destroy them. Cytokines, which are often secreted to promote inflammation, can be anti-inflammatory instead: for example, TGF-β and IL-10 are both secreted by senescent cells and discourage aggressive T cells and natural killer (NK) cells from destroying them [3, 4]. Similarly, an increase in certain inhibitory immune checkpoints, such as ones involving the programmed death (apoptosis)-related proteins PD-L1 and PD-1, block immune policing in a way that encourages senescence [5]. The author also noted that, on top of an increase in signals that inhibit immune cells from killing other cells (cytotoxicity), the cells themselves appear to be more receptive to these signals with aging.

Five key receptors

This paper focuses on these five specific receptors, explaining their functions and in what cells they appear.

PD-1 is primarily activated by PD-L1, which is common around the body [6]. While this protein is expressed by healthy cells, it is also strongly expressed by senescent cells and cancer cells, which use it to prevent being attacked by the immune system. While some cancers have managed to avoid attacks on this pathway [7], blocking this pathway may be a viable method of fighting senescence [5].

LILRB4 is also connected to cancer. An experiment in mice found that suppressing this pathway suppressed cancer [8]. However, activating the pathway instead may be a valid method of discouraging autoimmune issues, such as transplanted organ rejection [9]. In aging, LILRB4 is increasingly activated by increased fibronectin, and the literature suggests that it may be protective against conditions such as cardiac hypertrophy [10].

NKG2A is activated by HLA-E, a common protein expressed by cells that have been driven senescent by radiation or chemicals along with non-senescent cells exposed to the SASP [11]. Like other immunosuppressive receptors, cancers express HLA-E to avoid being consumed by the immune system [12].

TIM-3 has been documented to have multiple functions involving the suppression of the immune system. It has been linked to the exhaustion of some T cells while suppressing NK cells and inducing tolerance for transplants and antigens. It has multiple molecules that can activate it, including CEACAM1, which is produced by senescent cells [13].

SIRPα is activated by the CD47 protein, which increases with senescence. Blocking CD47 has been found to fight against atherosclerosis in mice [14]. This may be because CD47 inhibits macrophages from consuming cells that might need to be consumed, such as dying and dysfunctional cells [15]. It is a crucial “self” protein that differentiates the body’s cells from foreign invaders [16].

This is a particularly difficult area to target with drugs. Not only are there multiple potential targets, there is tremendous potential for harm whether they are underactivated or overactivated. By necessity, any research into this area must focus on getting immune cells to attack what they need to attack and leave alone what they need to leave alone.

Literature

[1] Salminen, A. (2021). Immunosuppressive network promotes immunosenescence associated with aging and chronic inflammatory conditions. Journal of Molecular Medicine, 99(11), 1553-1569.

[2] Ruhland, M. K., Loza, A. J., Capietto, A. H., Luo, X., Knolhoff, B. L., Flanagan, K. C., … & Stewart, S. A. (2016). Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis. Nature communications, 7(1), 11762.

[3] Li, M. O., Wan, Y. Y., Sanjabi, S., Robertson, A. K. L., & Flavell, R. A. (2006). Transforming growth factor-β regulation of immune responses. Annu. Rev. Immunol., 24(1), 99-146.

[4] Ouyang, W., Rutz, S., Crellin, N. K., Valdez, P. A., & Hymowitz, S. G. (2011). Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annual review of immunology, 29(1), 71-109.

[5] Wang, T. W., Johmura, Y., Suzuki, N., Omori, S., Migita, T., Yamaguchi, K., … & Nakanishi, M. (2022). Blocking PD-L1–PD-1 improves senescence surveillance and ageing phenotypes. Nature, 611(7935), 358-364.

[6] Acosta, J. C., Banito, A., Wuestefeld, T., Georgilis, A., Janich, P., Morton, J. P., … & Gil, J. (2013). A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nature cell biology, 15(8), 978-990.

[7] Vesely, M. D., Zhang, T., & Chen, L. (2022). Resistance mechanisms to anti-PD cancer immunotherapy. Annual review of immunology, 40(1), 45-74.

[8] Deng, M., Gui, X., Kim, J., Xie, L., Chen, W., Li, Z., … & Zhang, C. C. (2018). LILRB4 signalling in leukaemia cells mediates T cell suppression and tumour infiltration. Nature, 562(7728), 605-609.

[9] Xiang, Z., Yin, X., Wei, L., Peng, M., Zhu, Q., Lu, X., … & Zou, Y. (2024). LILRB4 Checkpoint for Immunotherapy: Structure, Mechanism and Disease Targets. Biomolecules, 14(2), 187.

[10] Zhou, H., Li, N., Yuan, Y., Jin, Y. G., Wu, Q., Yan, L., … & Tang, Q. Z. (2020). Leukocyte immunoglobulin-like receptor B4 protects against cardiac hypertrophy via SHP-2-dependent inhibition of the NF-κB pathway. Journal of Molecular Medicine, 98, 691-705.

[11] Pereira, B. I., Devine, O. P., Vukmanovic-Stejic, M., Chambers, E. S., Subramanian, P., Patel, N., … & Akbar, A. N. (2019). Senescent cells evade immune clearance via HLA-E-mediated NK and CD8+ T cell inhibition. Nature communications, 10(1), 2387.

[12] Fisher, J. G., Doyle, A. D., Graham, L. V., Khakoo, S. I., & Blunt, M. D. (2022). Disruption of the NKG2A: HLA-E immune checkpoint axis to enhance NK cell activation against cancer. Vaccines, 10(12), 1993.

[13] Sappino, A. P., Buser, R., Seguin, Q., Fernet, M., Lesne, L., Gumy-Pause, F., … & Mandriota, S. J. (2012). The CEACAM1 tumor suppressor is an ATM and p53-regulated gene required for the induction of cellular senescence by DNA damage. Oncogenesis, 1(4), e7-e7.

[14] Kojima, Y., Volkmer, J. P., McKenna, K., Civelek, M., Lusis, A. J., Miller, C. L., … & Leeper, N. J. (2016). CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis. Nature, 536(7614), 86-90.

[15] Logtenberg, M. E., Scheeren, F. A., & Schumacher, T. N. (2020). The CD47-SIRPα immune checkpoint. Immunity, 52(5), 742-752.

[16] Deuse, T., Hu, X., Agbor-Enoh, S., Jang, M. K., Alawi, M., Saygi, C., … & Schrepfer, S. (2021). The SIRPα–CD47 immune checkpoint in NK cells. The Journal of experimental medicine, 218(3).

A new study suggests that an anti-inflammatory diet can significantly reduce the risk of dementia and delay its onset even in people with existing cardiometabolic diseases [1].

Is it too late to lower the risk?

Cardiometabolic diseases, such as type 2 diabetes, heart attack, and stroke, strongly contribute to the risk of developing dementia later in life [2]. It is common wisdom that a healthy diet can help prevent or delay the onset of those diseases [3], but can it mitigate the risk of dementia after those co-morbidities have developed? That was the question that an international group of researchers from the US, Sweden, and China set out to answer in a new study.

The study was based on UK Biobank, a treasure trove of health data on hundreds of thousands of British citizens. The researchers built a sample of more than 80,000 adults over 60 who were dementia-free at baseline and were followed up for periods up to 15 years, with a median period of 12.4 years.

Several times over the course of the follow-up, the participants filled out an elaborate food questionnaire. This allowed the researchers to calculate a dietary inflammation score based on the reported intake of 31 ingredients. Inflammation is known to play a major role both in cardiometabolic diseases and in dementia.

Lower risk, later onset, and larger brains

During follow-up, close to 1,600 participants (1.9%) developed dementia. The presence of cardiometabolic diseases (CMDs) was predictably associated with a massive 81% increase in dementia risk. However, an anti-inflammatory diet mitigated this risk significantly: participants with CMDs who consumed an anti-inflammatory diet had a 31% lower risk of dementia compared to similar people who consumed a pro-inflammatory diet. Moreover, a pro-inflammatory diet increased the risk of dementia even in people without CMDs. In people who eventually developed dementia, an anti-inflammatory diet seemed to delay its onset by as much two years.

A subsample of 8,917 participants underwent MRI imaging during follow-up. The study revealed that an anti-inflammatory diet affected not just dementia risk but brain structure itself. In people with CMDs, an anti-inflammatory diet was associated with significantly larger total brain volume, grey matter volume, white matter volume, and white matter hyperintensity volume. The latter is the total volume of regions within the brain’s white matter that appear hyperintense, or brighter, on certain types of MRI scans. These hyperintensities have been linked to cognitive decline, stroke, and other cerebrovascular diseases.

What is an anti-inflammatory diet?

The researchers controlled for several possible confounding variables, including socioeconomic status, race and ethnicity, educational attainment, body-mass index, and various health parameters. They also ran several sensitivity analyses, such as excluding people who received a dementia diagnosis during the first five years of follow up and hence could have undiagnosed dementia at baseline.

The anti-inflammatory diets consumed in this study are generally based on fruits and vegetables, whole grains, unsaturated fats, and lean proteins. They emphasize fiber-rich foods, omega-3s, vitamin C, and polyphenols, and minimize saturated and trans fats. The Mediterranean diet is a good example of a low-inflammation diet. However, inflammatory responses to food can be highly individual, depending on factors like genetics, gut microbiota, and immune system sensitivity.

In this cohort study, participants with CMDs and an anti-inflammatory diet had a lower risk of dementia compared with those with a proinflammatory diet. Moreover, people with CMDs and an anti-inflammatory diet had significantly higher GMV and lower WMHV than their counterparts with a proinflammatory diet. Together, these results highlight an anti-inflammatory diet as a modifiable factor that may support brain and cognitive health among people with CMDs.

Literature

[1] Dove, A., Dunk, M. M., Wang, J., Guo, J., Whitmer, R. A., & Xu, W. (2024). Anti-Inflammatory Diet and Dementia in Older Adults With Cardiometabolic Diseases. JAMA Network Open, 7(8), e2427125-e2427125.

[2] Qiu, C., & Fratiglioni, L. (2015). A major role for cardiovascular burden in age-related cognitive decline. Nature Reviews Cardiology, 12(5), 267-277.

[3] Wang, W., Liu, Y., Li, Y., Luo, B., Lin, Z., Chen, K., & Liu, Y. (2023). Dietary patterns and cardiometabolic health: Clinical evidence and mechanism. MedComm, 4(1), e212.

A new study published in Aging Cell has detailed what happens to individual fat cells in white adipose tissue (WAT) as they age.

When fat is more than just fat

Previous research has described WAT as an organ in its own right, functioning not only as an energy storage source but as a regulator of metabolism [1]. If this function is impaired, adipose tissue moves towards the central abdomen [2]; causes fats to accumulate in other tissues, which leads to insulin resistance [3]; and leads to low-level chronic inflammation [4].

Like many other declines in function, this is related to aging. Cellular senescence [5], a lack of stem cell progenitors [6], and infiltration of immune cells into tissues [7] have all been pinpointed as potential causes.

However, those prior analyses were based on relatively primitive approaches, such as fluorescence imagery and relatively blunt cellular or tissue analysis. This research utilizes single-cell transcriptomics, a field that has recently been used to analyze human WAT [8]. As this team has recently used single-cell RNA sequencing on human fat cells [9], the researchers then chose to use that technique, in addition to others, in order to determine the effects of aging on these cells.

Fatter in the middle despite having the same BMI

This experiment drew samples from ten people who were at least 65 and ten more under the age of 30. Despite having similar metrics in insulin sensitivity and body mass, the older group had higher systolic blood pressure, greater waist circumference, and worse cholesterol measurements.

Analyzing the cells’ RNA to determine what genes were upregulated, the researchers initially found two groups of cells with differences that had little to do with aging. The first group, Adip_1, had upregulation of genes related to handling oxidation, while the second group, Adip_2, had upregulation of genes that were related to insulin responsiveness.

There were age-related differences in cell type and composition. Older people had more mast cells of connective tissue along with more macrophages associated with lipids, and these macrophages were of the M1 inflammatory type. Younger people’s stem cells produced more proteins related to the extracellular matrix, their vascular cells were more likely to create new blood vessels, and their Adip_2 cells had more active genes related to lipid metabolism.

Instead, in the older group, Adip_2 cells were more likely to have a gene expression profile associated with increased inflammation, and many cells in older people produced collagen that was associated with fibrosis and a lack of insulin sensitivity [10]. Fibrosis itself was, fortunately, not found to be increased with aging in WAT. Older people did, however, have more very large fat cells than younger people did.

Macrophages in the gut

Macrophage infiltration was visible under the microscope. In older males, macrophages attacking damaged or dying adipocytes would form crown-like structures in the process. This was very strongly associated with the accumulation of fat in the abdominal area. In particular, CXC14 was singled out as a key driver of inflammation and macrophage infiltration [11], and it was found to be upregulated in older people.

Unsurprisingly, older people had significantly increased levels of cellular senescence in WAT. Rather than being general among all cell types, though, pre-adipocytes, Adip_1 cells, and vascular tissues were noted as producing senescence-related proteins.

This study was illuminating for future work, associating previously unassociated biological metrics with inflammation and senescence. Fat accumulating in the gut is not just something that happens: it appears to be the result of the fat tissue, itself, suffering from inflammaging.

Literature

[1] Goodpaster, B. H., & Sparks, L. M. (2017). Metabolic flexibility in health and disease. Cell metabolism, 25(5), 1027-1036.

[2] Kuk, J. L., Saunders, T. J., Davidson, L. E., & Ross, R. (2009). Age-related changes in total and regional fat distribution. Ageing research reviews, 8(4), 339-348.

[3] Boren, J., Taskinen, M. R., Olofsson, S. O., & Levin, M. (2013). Ectopic lipid storage and insulin resistance: a harmful relationship. Journal of internal medicine, 274(1), 25-40.

[4] Starr, M. E., Evers, B. M., & Saito, H. (2009). Age-associated increase in cytokine production during systemic inflammation: adipose tissue as a major source of IL-6. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 64(7), 723-730.

[5] Justice, J. N., Gregory, H., Tchkonia, T., LeBrasseur, N. K., Kirkland, J. L., Kritchevsky, S. B., & Nicklas, B. J. (2018). Cellular senescence biomarker p16INK4a+ cell burden in thigh adipose is associated with poor physical function in older women. The Journals of Gerontology: Series A, 73(7), 939-945.

[6] Caso, G., McNurlan, M. A., Mileva, I., Zemlyak, A., Mynarcik, D. C., & Gelato, M. C. (2013). Peripheral fat loss and decline in adipogenesis in older humans. Metabolism, 62(3), 337-340.

[7] Trim, W. V., Walhin, J. P., Koumanov, F., Bouloumié, A., Lindsay, M. A., Chen, Y. C., … & Thompson, D. (2022). Divergent immunometabolic changes in adipose tissue and skeletal muscle with ageing in healthy humans. The Journal of physiology, 600(4), 921-947.

[8] Divoux, A., Whytock, K. L., Halasz, L., Hopf, M. E., Sparks, L. M., Osborne, T. F., & Smith, S. R. (2024). Distinct subpopulations of human subcutaneous adipose tissue precursor cells revealed by single-cell RNA sequencing. American Journal of Physiology-Cell Physiology, 326(4), C1248-C1261.

[9] Whytock, K. L., Divoux, A., Sun, Y., Hopf, M., Yeo, R. X., Pino, M. F., … & Sparks, L. M. (2023). Isolation of nuclei from frozen human subcutaneous adipose tissue for full-length single-nuclei transcriptional profiling. STAR protocols, 4(1), 102054.

[10] Divoux, A., Tordjman, J., Lacasa, D., Veyrie, N., Hugol, D., Aissat, A., … & Clément, K. (2010). Fibrosis in human adipose tissue: composition, distribution, and link with lipid metabolism and fat mass loss. Diabetes, 59(11), 2817-2825.

[11] Lu, J., Chatterjee, M., Schmid, H., Beck, S., & Gawaz, M. (2016). CXCL14 as an emerging immune and inflammatory modulator. Journal of Inflammation, 13, 1-8.