Apoptosis, autophagy and senescence
Autophagy is a cleanup process that causes the removal of aggregated or misfolded proteins an also the recycling of damaged cell components, plays a big role in this. Autophagy is up-regulated by fasting and CR and has a protective part against genome instability and necrosis. By and large, it has a substantial role in prevention of many diseases like infections, diabetes, cancer, autoimmune diseases and others,
Apoptosisis an orderly process in which the cell’s contents are packaged into small packets of membrane for “garbage collection” by immune cells.Apoptosisremoves cells during development, eliminates potentially cancerous and virus-infected cells, and maintains balance in the body.
Cellular senescence is one phenomenon by which normal cells cease to divide. In the 1960’s, Leonard Hayflick and Paul Moorhead found out that normal human fetal fibroblasts in culture reach a maximum of approximately 50 cell population doublings before becoming senescent. Senescence can be induced by such stresses as telomere shortening, DNA damage, oncogenic mutations, metabolic and mitochondrial dysfunction, and inflammation. Senescent cell burden increases in multiple tissues with aging, at sites of pathology in multiple chronic diseases, and after radiation or chemotherapy.
Senescent cells (SC) play a big role in the process of aging and for age-related physical dysfunctions. SC are very different from healthy cells. The expression of different genes, no more replication and the increased production of pro-inflammatory signals are characteristics. Such signaling substances are f.i. inflammatory promoting cytokines, chemokines, and built together the so called senescence-associated secretory phenotype (SASP). The inflammation created by SC can lead to tissue dysfunction and as well can turn healthy cells senescent.
Senescence cells have several pathways to escape apoptosis. This is where senolytics come into play. Xu and colleagues found out, that a mix of dasatinib and quercetin (flavonoid) selectively eliminate SC and so alleviated physical dysfunction an late-life survival in mice. Now a number of pharmaceuticals and function foods/ additives and especially caloric restriction / fasting are investigated for their effects to reduce senescence cells from tissues. This would have a deep impact on longevity, health with economic aspects.
Metabolic pathways in aging, fasting, IGF, insulin signalling and SIRT
When food is ingested, growth hormones (GH) are released and activate the insulin an IGF-1 signalling pathway to provide cells with information about the glucose status, allowing them to react accordingly. A constant activation of this metabolic pathway can be harmful to the organism. Mammals with a genetic polymorphism that reduces GH and IGF-1 signalling have shown to have increased lifespan and a better ability to resist stress conditions.
Fasting leads to a reduction of anabolic pathways and induces catabolic signalling (e.g. AMPK, FOXO and sirtuins). For instance, SIRT 1 shows positive effects by triggering the metabolic switch and turning endogenous fatty acids into the main source of energy. AMPK is activated by sensing low levels of AMP and blocks mTOR which leads to stimulation of autophagy and interaction with SIRT1 to a positive feedback loop.molecules.stem cell functions
Whereas high level of ROS (radical oxygen species) accelerate aging, low levels of ROS seem to be necessary to continue the state of quiescence and the self-renewal ability. Fasting can decrease ROS through ketogenic metabolism.
