We will summarize the scientific data of how stressors can affect senescence on the cellular level before we delve into each mechanism of “stress induced premature senescence (SIPS)”. Here “stress” is broadly defined to include all external environmental factors (stressors) that contribute or accelerate the aging process. These mechanisms include: accelerated aging caused by exogenous free radicals and ROS stressors from exposure to diet, chemical or UV sun light and other radiations, toxic chemicals (e.g. heavy metal), exogenous glycating agents and AGE from diet, behavioral and psychological stress. We will explore the cascade events of changes triggered by these stressors including stress induced crosslinking (methylation, glycation and other types of crosslinking), stress induced DNA damage/mutation, stress induced changes in gene expressions and the consequence of these induced gene expressions, stress induced mitochondrion damage and excess inflammation.
Different cell lines can be cultured in the presence of various stressors to study stress induced cellular senescence. Cells cultured in the presence of 50% O2 is highly toxic. Other sources of oxidative damage, such as H2O2 and tert-butylhydroperoxide, and other stressors–e.g., ethanol, ionizing radiations, and mitomycin C–can induce SIPS in many types of proliferative cells such as lung and skin fibroblasts, endothelial cells, melanocytes, and retinal pigment epithelial cells. The list of stressors that can cause SIPS is constantly growing. Instead of chronic stress, SIPS can also be induced based on a single or repeated short exposure(s) to stressors.
Depending on the dose of stressor used, a cell culture population will react in different ways and have different fate – proliferation, senescence, apoptosis, or necrosis. For instance, a high cytotoxic dosage of a stressor causes such an amount of damage that cellular biochemical activities decrease leading to cellular death by necrosis. The level of damage sustained by cells determines whether programmed cell death–apoptosis–can unfold or, if the damage is even lower, senescence. Since a cellular population is not homogeneous, the dose of the stressor will shift the percentage of cells executing each of the possible programs depending, respectively, on the amount of stressor. In order for SIPS to occur, a precise subcytotoxic dose must be determined for each cell culture population.
UV and other radiation induced premare aging
It is well-established that long-term, sunlight-induced damage causes wrinkles and skin aging. Although gerontologists think that the normal or intrinsic aging process is probably not the same as photoaging, there are enough similarities to make this a tantalizing field of study. UV-A light creates mostly free radicals which in turn can trigger DNA damage. UV-B light and Radiations can cause DNA damage directly.
Photoaging damages skin collagen and elastin, keratinocytes, affect melanocytes. Visit our skin aging part for the mechanism of UV/Radiation induced skin aging for more detailed explanation.
UV-B light causes crosslinking between adjacent cytosine and thymine bases of DNA molecules, creating pyrimidine dimers. Ionizing radiation such as that created by radioactive decay or in cosmic rays causes breaks in DNA strands.
Exogenous Glycation and AGE formation
Exposure to toxic chemicals
Industrial chemicals such as vinyl chloride and hydrogen peroxide, and environmental chemicals such as polycyclic hydrocarbons found in smoke, soot and tar create a huge diversity of DNA adducts- ethenobases, oxidized bases, alkylated phosphotriesters and Crosslinking of DNA just to name a few.
Temperature
Thermal disruption at elevated temperature increases the rate of depurination (loss of purine bases from the DNA backbone) and single strand breaks. For example, hydrolytic depurination is seen in the thermophilic bacteria, which grow in hot springs at 85–250 °C. The rate of depurination (300 purine residues per genome per generation) is too high in these species to be repaired by normal repair machinery, hence a possibility of an adaptive response cannot be ruled out.
Behavioral and Psychological stress
The role of heat shock protein in response to various stress and aging
Despite their name, heat shock proteins (HSPs) are produced when cells are exposed to various stresses, not only heat. Their expression can be triggered by exposure to toxic substances such as heavy metals and chemicals and even by behavioral and psychological stress. What attracts aging researchers to HSPs is the finding that the levels at which they are produced depend on age. Old animals placed under stress—short term, physical restraint, for example—have lower levels of a heat shock protein designated HSP-70 than young animals under similar stress. Moreover, in laboratory cultures of cells, researchers have found a striking decline in HSP-70 production as cells approach senescence. Exactly what role HSPs play in the aging process is not yet clear. They are known to help cells dismantle and dispose of damaged proteins. They also facilitate the making and transport of new proteins. But what proteins are involved and how they relate to aging is still the subject of speculation and study. While at the NIA (national institute of aging), researchers investigated the action of HSP-70 in specific sites, such as the adrenal cortex (the outer layer of the adrenal gland). In this gland as well as in blood vessels and possibly other sites, the expression of HSP-70 appears closely related to hormones released in response to stress, such as the glucocorticoids and catecholamines. Eventually, answers to the puzzle of HSPs may throw light on some parts of the neuroendocrine system, whose hormones and growth factors might have an important influence on the aging process.
Stress induced gene expressions
Explain how external stress signal was transducted into the cell nuclear and interact with gene expression machinery and trigger or change the expression of genes, and in turn affect our aging process. Free radicals initiate changes that unbind NF-kappaB in the cytoplasm of cells, so that it translocates to the cell’s nucleus where it binds to the DNA and initiates inflammatory responses.
