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    Exosomes to rejuvenate senescent cells


    Senescence means “the process of aging” and in this sense is defined as the period of gradual decline that follows the developmental phase in the life of an organism.

    Elderly population has heavily increased worldwide in the last few decades, and as a consequence of that, conditions and illness related with aging has also dramatically increased: cancer, neurodegenerative and cardiovascular diseases are some of these kinds of conditions which are more and more commonly diagnosed.

    In this sense, researchers all over the world are focusing all their effort in improving the methods and understanding of these diseases, their possible solutions and faster diagnosis in order to help stopping these tendencies and senescence processes role on this mix.

    What are senescent cells and why are they important?

    Cellular senescence refers to a state of stable cell cycle arrest in which proliferating cells become resistant to growth-promoting stimuli, typically in response to DNA damage.

    It is now generally accepted that only transformed malignant cells replicate indefinitely, whereas non-transformed cells do not, but there are exceptions that include cell types with stem cell-like properties. In this sense, senescent cells are distinct from both quiescent cells that can re-enter the cell cycle and terminally differentiated cells.

    Senescent process is important because the occurrence of senescence have been described to contribute to many of the age-associated pathologies that we have previously mentioned: cancer, tissue degeneration and inflammatory diseases.

    What does senescence have to be with aging?

    First of all, it is important to understand that aging and cellular senescence are not the same thing, and that these terms cannot be used indiscriminately. But then what is senescence? Can we use senescence cells in order to help slowing aging? Below we are going to point out the main differences between the concepts of senescence and aging:

    ►  On the one hand, aging is a progressive decrease over time, while senescence happens throughout life, including during embryogenesis.

    Additionally, the number of senescent cells increases with age, but senescence also plays an important role during development, as well as during wound healing.

    ►  Moreover, senescence prevents the replication of cells harboring damaged DNA, which serves an important anti-tumor function.

    ►  And finally, senescence often occurs in response to detrimental stimulation, such as telomere shortening (replicative senescence), DNA damage (DNA damage-induced senescence) and oncogenic signaling (oncogene-induced senescence).

    What do senescent cells do? Why are senescent cells bad?

    Senescent cells have a special characteristic and it is that they suddenly stop multiplying, but they do not die when they should, which may cause several health problems.

    This means that when instead of die and follow their natural process they can remain and keep releasing chemicals that can promote inflammation. In this sense, it can be very dangerous because if senescent cells persist and spread this inflammation this can trigger an important damage in neighboring cells.

    In this sense, to the question why are senescent cells bad? Well, they can cause some important issues as we have already seen but… the truth is that not all senescent cells are bad: some molecules and compounds expressed by senescent cells play important roles throughout life, including in embryonic development, childbirth, and wound healing, among others.

    When does senescence begin?

    The biological role of senescence is complicated, as both protective and detrimental effects of senescent cells have been described, and in any case, this will depend on the physiological context.

    For instance, while senescence has probably evolved as a mechanism to prevent malignant transformation of damaged cells, the occurrence of senescence may contribute to many of the age-associated pathologies mentioned above: cancer, tissue degeneration, and inflammatory diseases.

    Thus, senescence in humans would begin sometime in their 20s, at the peak of their physical strength, and continue for the rest of their lives.

    How are senescent cells die?

    As we have previously addressed, senescent cells usually die themselves via a programmed process called apoptosis, as all types of cells.

    However, the immune system becomes weaker with aging, and in this process, an increasing number of senescent cells eludes this process of apoptosis and therefore begins to aggregate in all body tissues.

     When people reach old age, a significant number of these senescent cells have accumulated, causing chronic inflammation and damage surrounding cells and tissues.

    And this is the reason why, the accumulation of senescent cells is thought to be one of the proposed reasons for aging.

    How are senescent cells removed?

    As a solution to the problem that we have been addressing before about senescent cell accumulation and the resulting diseases and problems that causes, there have been several options researched during the last decades.

    In this sense, various studies on animals have shown that removing some senescent cells can be beneficial to prevent health problems, and therefore, increasing quality of life while aging.

    Why are interesting exosomes released by senescent cells?

    As we have already seen in previous articles, exosomes carry biological material in the form of proteins, RNA or small RNAs called microRNAs.

    In this sense, exosomes can release their inner contents into certain cells, which as a consequence induce changes in the target cells.

    It has been shown in several studies that senescent cells release a high number of exosomes inducing senescence in neighboring cells.

    This is why the study of the internal content of these specific exosomes, in addition to the internal content of exosomes secreted by cells  from elderly patients, becomes a key approach for the treatment and diagnosis of aging-related diseases.

    In the face of such research, it is important to note that not all senescent cells display all senescence biomarkers. Furthermore, senescence biomarkers are not necessarily specific to senescent cells, as some markers are observed in apoptotic cells or quiescent cells, for example. Therefore, the identification of senescent cells depends on the observation of several biomarkers.

    What is the role of circulating EVs and exosomes in aging?

    As we have mentioned above, cellular senescence is a tumor suppressor mechanism that permanently arrests cells at risk of malignant transformation. However, there is increasing evidence that senescent cells can have deleterious effects on the tissue microenvironment.

    The most significant of these effects is the acquisition of a senescence-associated secretory phenotype (SASP) that converts senescent fibroblasts into proinflammatory cells that have the ability to promote tumor progression.

    During human aging, levels of circulating proinflammatory cytokines such as IL-6, IL-8 and tumor necrosis factor-alpha, which are associated with an increased likelihood of acquiring certain diseases, such as inflammatory and metabolic diseases, are elevated.

    Among these cytokines, the circulating concentration of IL-6, an important factor in SASP, has been well studied. Serum IL-6 levels increase with age and may be associated with mortality in the elderly.

    And, in this regard, the accumulation of senescent cells with age may influence the release and content of circulating EVs. Although some SASP factors increase in the blood with aging, it remains unclear whether senescence associated EVs increase in the blood with age.

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