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Can we target the immune cells to ameliorate the ageing phenotype?

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Antonio Carusillo
Antonio Carusillo Dec 03, 2020
Why the Immune system and what is Immune-Senescence?

Aging is associated with a progressive decline of physiological functions and the onset of pathological conditions. Among the different cell types composing the human body, the ones belonging to the immune system are no exception. This process has been properly defined as immune-senescence and it embodies the changes in the functionality of the immune cells .
Interestingly, immune-senescence phenotype doesn’t translate in the total loss of function of immune cells, but rather in a loss and gain. For example, while chemotaxis and proliferation functions are impaired, on the other hand, others like ROS production have been reported to increase . Inflammatory compounds and ROS are part of the arsenal of the immune cells to cover their role as a defense system. In particular, phagocytes like neutrophils and macrophages produce a great amount of ROS to kill pathogens and tumor cells as well. However, in healthy cells, ROS are known to be mutagenic and an excessive ROS release is associated with an increased oxidative stress and it may increase the cell DNA damage burden, which, if unbearable, may contribute and speed up the aging process . For these reasons, fully functional immune cells, usually, along with releasing ROS and inflammatory compounds, can also release antioxidant molecules and anti-inflammatory compounds, thus, maintaining a fine balance between oxidant and antioxidant, inflammation and anti-inflammation .

The oxidative-inflammatory theory

If this balance is deregulated, it may trigger a detrimental oxidation-inflammation circle. For example, excessive ROS release can activate the NF-kB pathway which in turns stimulates the release of inflammatory cytokines from immune cells .
For this reason, an “oxidative-inflammatory theory” has been proposed . This suggests that the age-related oxidative-inflammatory stress affects all cells, but especially those of the regulatory systems, such as the nervous, endocrine, and immune systems, resulting in an impairment of their functions, as well as the communication between them. It also highlights the importance of senescent immune cells in this context and their role in accelerating the aging process of the organism. It is important to note that phagocytes, such as macrophages and neutrophils, have been proposed to be the main cells responsible for the chronic oxidative-inflammatory stress associated with immunosenescence. Thus, as a result of the age-related oxidative injury, these cells could lose their capacity to regulate their redox and inflammatory balance, producing more and more oxidant and inflammatory compounds, and therefore, contributing to the increased oxidative-inflammatory stress observed in other physiological systems with aging.

Lipofuscin: the hallmark of aging

Lipofuscin accumulation is considered as one of the best “hallmarks of aging” because lipofuscin increases with age and the rate of lipofuscin accumulation correlates negatively with longevity. Lipofuscin and lipofuscin-like compounds can be considered as aggregates of undigested cell materials. Accumulation of lipofuscin in postmitotic cells seems to lead to a variety of defects in cellular functions and homeostasis. Also, this compound cannot be digested, thus, its accumulation progressively impairs the lysosomal function, and it leads to alterations in both phagocytosis and autophagy processes, which may have dramatic consequences on cell physiology. Finally, it has been observed that an increased abundance of lipofuscin may stimulate the release of proinflammatory chemokines and cytokines .

Role of Macrophages

In an example study , the role of macrophages in oxidative-inflammation loop installation has been investigated in old mice. In particular, peritoneal macrophages have been studied for physiological change due to age-related phenotypes like oxidative stress and lipofuscin accumulation. The results of this study provided evidence for peritoneal leukocytes from old mice, and especially macrophages, having an increased oxidative stress, high accumulation of lipofuscin, and impaired immune functions. Higher accumulation of lipofuscin, as well as the impairment of both phagocytosis and digestive capacity was observed in the aged macrophages. Moreover, it is important to note that macrophages of old mice showed higher XO activity and accumulation of lipofuscin than the lymphocytes, suggesting that phagocytic cells could contribute in a relevant manner to the oxidative stress and damage associated with immunosenescence.

Open Questions:

This and other studies point at the immune system and macrophages, in particular, as key players in the aging process. My questions are:

  1. Which are the current approaches targeting the immune system to address aging?
  2. Which are possible new approaches we may devise to this goal?
  3. Which are other possible immune cells we may target to ameliorate the aging phenotype?

[1]Aiello Anna, Farzaneh Farzin, Candore Giuseppina, Caruso Calogero, Davinelli Sergio, Gambino Caterina Maria, Ligotti Mattia Emanuela, Zareian Nahid, Accardi Giulia; Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention Frontiers in Immunology, vol. 10 2019 DOI=10.3389/fimmu.2019.02247

[2]De la Fuente M. (2014) The Immune System, a Marker and Modulator of the Rate of Aging. In: Massoud A., Rezaei N. (eds) Immunology of Aging. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-39495-9_2

[3]Glyn Nelson, Olena Kucheryavenko, James Wordsworth, Thomas von Zglinicki, The senescent bystander effect is caused by ROS-activated NF-κB signalling, Mechanisms of Ageing and Development, Volume 170, 2018, Pages 30-36, ISSN 0047-6374, https://doi.org/10.1016/j.mad.2017.08.005.

[4]De la Fuente M. (2018) Oxidation and Inflammation in the Immune and Nervous Systems, a Link Between Aging and Anxiety. In: Fulop T., Franceschi C., Hirokawa K., Pawelec G. (eds) Handbook of Immunosenescence. Springer, Cham. https://doi.org/10.1007/978-3-319-64597-1_115-1

[5]Lingappan K. NF-κB in Oxidative Stress. Curr Opin Toxicol. 2018;7:81-86. doi:10.1016/j.cotox.2017.11.002

[6]De la Fuente M, Miquel J. An update of the oxidation-inflammation theory of aging: the involvement of the immune system in oxi-inflamm-aging. Curr Pharm Des. 2009;15(26):3003-26. doi: 10.2174/138161209789058110. PMID: 19754376.

[7]Moreno-García A, Kun A, Calero O, Medina M, Calero M. An Overview of the Role of Lipofuscin in Age-Related Neurodegeneration. Front Neurosci. 2018;12:464. Published 2018 Jul 5. doi:10.3389/fnins.2018.00464

[8]Carmen Vida, Irene Martínez de Toda, Julia Cruces, Antonio Garrido, Mónica Gonzalez-Sanchez, Mónica De la Fuente, Role of macrophages in age-related oxidative stress and lipofuscin accumulation in mice, Redox Biology, Volume 12, 2017, Pages 423-437, ISSN 2213-2317, https://doi.org/10.1016/j.redox.2017.03.005.

[9]Lloberas J., Tur J., Vico T., Celada A. (2019) Molecular and Cellular Aspects of Macrophage Aging. In: Fulop T., Franceschi C., Hirokawa K., Pawelec G. (eds) Handbook of Immunosenescence. Springer, Cham. https://doi.org/10.1007/978-3-319-99375-1_46

[10]Connie Jackaman, Federica Tomay, Lelinh Duong, Norbaini Bintu Abdol Razak, Fiona J. Pixley, Pat Metharom, Delia J. Nelson, Aging and cancer: The role of macrophages and neutrophils, Ageing Research Reviews, Volume 36, 2017, Pages 105-116, ISSN 1568-1637, https://doi.org/10.1016/j.arr.2017.03.008.

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