“What are ‘zombie‘ cells?”
“They’re called zombie cells, because they are damaged and refuse to die.”
“As we age, these damaged cells start to accumulate and cause sterile inflammation which can alter metabolism and stem cell function, promoting aging and the conditions that are often associated with it, like Alzheimer’s disease. These zombie cells are formally called, senescent cells. When the cells get to a certain level of damage, they go through an aging process of their own called cellular senescence. When cells become damaged or if they replicate too many times, they undergo a process of irreversible removal from the cell cycle and start releasing inflammatory factors that stimulate the immune response to clear the damaged cells. A younger person’s immune system is healthy and is able to clear the damaged cells, but as people age, they aren’t cleared as effectively and they accumulate causing potential problems.”
“Senescent cells display a “zombie”-like behavior known as a senescence-associated secretory phenotype (SASP). In this death-defying, zombie-like state, the cells ramp up their release of proteins, bioactive lipids, DNA, and other factors that, like a zombie virus, induce nearby healthy cells to join in the dysfunction.”
“Could killing off these ‘zombie‘ cells in the mice delay their premature descent into old age? The answer was yes. In a 2011 study, the team found that eliminating these ‘senescent‘ cells forestalled many of the ravages of age. The discovery set off a spate of similar findings. In the seven years since, dozens of experiments have confirmed that senescent cells accumulate in ageing organs, and that eliminating them can alleviate, or even prevent, certain illnesses (see ‘Becoming undead’). This year alone, clearing the cells in mice has been shown to restore fitness, fur density and kidney function. It has also improved lung disease and even mended damaged cartilage. And in a 2016 study, it seemed to extend the lifespan of normally aging mice.”
Want to live for ever? Flush out your zombie cells
“To date about a dozen drugs have been reported that can mop up zombie cells. Clearance of the cells in mice has been shown to delay or alleviate everything from frailty to cardiovascular dysfunction to osteoporosis to, most recently, neurological disorders – though whether killing senescent cells extends life is complicated. Most of the benefit seen in mice seems to be in extending healthspan, the time free of frailty or disease, and as a result median lifespan (being sick, after all, is risky). True longevity – the maximum time the animals remain alive for – remains relatively unchanged, though studies published in July and September 2018 show an extension of remaining lifespan in mice that were treated when they were very old.”
Zombie cells found in brains of mice prior to cognitive loss
Zombie cells are the ones that can’t die but are equally unable to perform the functions of a normal cell. These zombie, or senescent, cells are implicated in a number of age-related diseases. “Senescent cells are known to accumulate with advancing natural age and at sites related to diseases of aging, including osteoarthritis; atherosclerosis; and neurodegenerative diseases, such as Alzheimer’s and Parkinson’s,” says Darren Baker, Ph.D., a Mayo Clinic molecular biologist and senior author of the paper. “In prior studies, we have found that elimination of senescent cells from naturally aged mice extends their healthy life span.”
Removal of ‘zombie cells’ alleviates causes of diabetes in obese mice
Mayo Clinic researchers and their collaborators have shown that when senescent cells — also known as “zombie cells” — are removed from fat tissue in obese mice, severity of diabetes and a range of its causes or consequences decline or disappear.
Inflammation and dysfunction of fat tissue cause some of the insulin resistance in obese people. In many cases, that dysfunction is caused by zombie cells that already have been shown to be responsible for conditions related to aging and illness, including osteoporosis, muscle weakness, nerve degeneration and heart disease. These cells also accumulate in the fat tissues of obese and diabetic people and mice.
In this study, the researchers, using genetically modified mice and wild-type (normal) mice, removed zombie cells two ways: by causing genetically-mediated cell death and by administering a combination of senolytic drugs. Senolytic drugs selectively kill senescent cells but not normal cells. The result: Glucose levels and insulin sensitivity improved. The mice also showed a decline in inflammatory factors and a return to normal fat cell function.
“Zombie” Cells and Clinical Biomarkers of Aging
Briefly, cellular senescence is a process whereby cells stop dividing and go through phenotypic changes, such as secretome and chromatin changes in addition to tumor-suppressor activation. Senescent cells accumulate in several organs as we grow older, are involved in tissue dysfunction and implicated in numerous pathologies such as cancer. Therefore, they are generally considered to be a “hallmark” of aging and have earned the nickname “zombie” cells.
‘Zombie’ cells signal death of tissue in Alzheimer’s
Cellular senescence allows the stressed cell to survive, but the cell may become like a zombie, functioning abnormally and secreting substances that kill cells around it. “When cells enter this stage, they change their genetic programming and become pro-inflammatory and toxic,” said study senior author Miranda E. Orr, Ph.D. She is a VA research health scientist at the South Texas Veterans Health Care System, faculty member of the Sam and Ann Barshop Institute for Longevity and Aging Studies, and instructor of pharmacology at UT Health San Antonio. “Their existence means the death of surrounding tissue.” The team reported the discovery in the journal Aging Cell. To clear senescent cells from the brains of middle-aged mice with advanced brain disease, researchers used a combination of drugs called senolytics.
SCIENTISTS: DRUGS THAT KILL “ZOMBIE CELLS” COULD PREVENT AGING
Doctors trying to eradicate age-related diseases have a new target: “zombified” senescent cells that can build up in people’s brains after an infection or stress. Most of the research that links senescent cells to conditions like Alzheimer’s disease, diabetes, and osteoporosis was conducted in mice, according to the Associated Press. But in February, a new experiment suggested that clearing senescent cells from humans with a fatal lung condition improved their well-being — a finding that gives anti-aging scientists and advocates new hope on their quest to keep people alive and healthy longer than ever before.
A brief history of senolytics
The health and lifespan of mice have been demonstrated to improve by the removal of senescent cells using a transgenic suicide gene [3], and additional experiments showed that the same could be achieved using small molecules.Senescent cells comprise a small number of total cells in the body, but they secrete pro-inflammatory cytokines, chemokines, and extracellular matrix proteases, which, together, form the senescence-associated secretory phenotype, or SASP. The SASP is thought to significantly contribute to aging [4] and cancer [5]; thus, senolytics and the removal of the SASP are a potential strategy for promoting health and longevity.
It was discovered through transcript analysis that senescent cells have increased expression of pro-survival genes consistent with their resistance to apoptosis [6]. Drugs targeting these pro-survival factors selectively killed senescent cells. Two such drugs were dasatinib and quercetin, which were both able to remove senescent cells but were better in different tissue types. However, it was discovered that a combination of the two drugs formed a synergy that was significantly more effective at removing some senescent cell types [7].In other studies, removing only thirty percent of senescent cells was sufficient to slow down age-related decline. These results suggest the feasibility of selectively ablating senescent cells and the efficacy of senolytics in alleviating the diseases of aging and promoting healthy longevity [8, 9, 10].
Further confirming the potential of senolytics to treat age-related disease, a recent study demonstrated the benefits of senolytics for certain aspects of vascular aging [11]. This was the first study to show that clearance of senescent cells improves aspects of vascular aging and chronic hypercholesterolemia, thus making senolytics a possible viable method of reducing morbidity and mortality from cardiovascular diseases. Even more recently, progress has been made in treating atherosclerosis using senolytics to address the “foam cells” that contribute to this disease [12]. There has also been progress in ways to treat type 2 diabetes using senescent cell removal [13]. Senolytics also have the potential for slowing skin aging [14] and treating osteoarthritis [15].
Senescent cells, however, are not all bad, and evidence shows that they play a role in cellular reprogramming [16] and wound healing. Like all things in biology, it is therefore clearly a question of balance: too much clearance of senescent cells would be bad for wound healing and cellular reprogramming, but too many senescent cells lead to damage [17, 18]. Therefore, the key to developing effective senolytic therapies that combat the diseases of aging is the creation of even more accurate biomarkers to measure senescent cell numbers in tissue [19] combined with effective delivery methods for the selective removal of senescent cells.
Senolytic Therapies And The Quest To Cure Aging
Though the term “senolytic therapies” may be a bit foreign to the general public, the agents themselves are nothing new to scientists who have been looking to them to find treatments for a host of ailments that cause human beings to age. “Senolytic compounds are those that preferentially destroy senescent cells. Since these cells are one of the root causes of aging, there is considerable interest in finding and then quantifying the effectiveness of senolytic compounds…
The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs
The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and the burden of age‐related chronic diseases. Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells. By transcript analysis, we discovered increased expression of pro‐survival networks in senescent cells, consistent with their established resistance to apoptosis. Using siRNA to silence expression of key nodes of this network, including ephrins (EFNB1 or 3), PI3Kδ, p21, BCL‐xL, or plasminogen‐activated inhibitor‐2, killed senescent cells, but not proliferating or quiescent, differentiated cells. Drugs targeting these same factors selectively killed senescent cells. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse BM‐MSCs. The combination of dasatinib and quercetin was effective in eliminating senescent MEFs. In vivo, this combination reduced senescent cell burden in chronologically aged, radiation‐exposed, and progeroid Ercc1−/Δ mice. In old mice, cardiac function and carotid vascular reactivity were improved 5 days after a single dose. Following irradiation of one limb in mice, a single dose led to improved exercise capacity for at least 7 months following drug treatment. Periodic drug administration extended healthspan in Ercc1−/∆ mice, delaying age‐related symptoms and pathology, osteoporosis, and loss of intervertebral disk proteoglycans. These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan.
What is the relationship between COVID-19 and advanced chronological age?
“Here, we suggest that the COVID-19 corona virus preferentially targets senescent lung cells, resulting in increased morbidity and mortality in the aging population. One possible solution for prevention/treatment would be the use of senolytics or other anti-aging drugs.”
“What is THE “SASP“?”
“Social Life” of Senescent Cells: What Is SASP and Why Study It?
Cellular senescence was first described as a failure of normal human cells to divide indefinitely in culture. Until recently, the emphasis in the study of cell senescence has been focused on the accompanying intracellular processes. The focus of the attention has been on the irreversible growth arrest and two important physiological functions that rely on it: suppression of carcinogenesis due to the proliferation loss of damaged cells, and the acceleration of organism aging due to the deterioration of the tissue repair mechanism with age. However, the advances of the past years have revealed that senescent cells can impact the surrounding tissue microenvironment, and, thus, that the main consequences of senescence are not solely mediated by intracellular alterations. Recent studies have provided evidence that a pool of molecules secreted by senescent cells, including cytokines, chemokines, proteases and growth factors, termed the senescence-associated secretory phenotype (SASP), via autocrine/paracrine pathways can affect neighboring cells. Today it is clear that SASP functionally links cell senescence to various biological processes, such as tissue regeneration and remodeling, embryonic development, inflammation, and tumorigenesis. The present article aims to describe the “social” life of senescent cells: basically, SASP constitution, molecular mechanisms of its regulation, and its functional role.
The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression
Cellular senescence is a tumor-suppressive mechanism that permanently arrests cells at risk for malignant transformation. However, accumulating evidence shows 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 turns senescent fibroblasts into proinflammatory cells that have the ability to promote tumor progression.
THE SECRETORY PHENOTYPE OF SENESCENT CELLS
The senescent phenotype is not limited to an arrest of cell proliferation. In fact, a senescent cell is a potentially persisting cell that is metabolically active and has undergone widespread changes in protein expression and secretion, ultimately developing the SASP. This phenotype has also been termed the senescence-messaging secretome (35). We recently provided a large-scale characterization of the SASP, using antibody arrays to quantitatively measure factors secreted by human fibroblasts and epithelial cells (18), as well as mouse fibroblasts (J.P. Coppé & J. Campisi, unpublished data). The potential existence of the SASP was already suggested by large-scale comparative gene (mRNA) expression studies performed on fibroblasts from different-aged donors and different tissues of origin (36–46). Among the cells that have been shown to senesce and secrete biologically active molecules are liver stellate cells (47), endothelial cells (36, 48–51), and epithelial cells of the retinal pigment, mammary gland, colon, lung, pancreas, and prostate (8, 18, 36, 41, 52–56).
Senescence-associated changes in gene expression are specific and mostly conserved within individual cell types. Most differences between the molecular signatures of presenescent and senescent cells entail cell-cycle- and metabolism-related genes, as well as genes encoding the secretory proteins that constitute the SASP. The SASP includes several families of soluble and insoluble factors (see Table 1). These factors can affect surrounding cells by activating various cell-surface receptors and corresponding signal transduction pathways that may lead to multiple pathologies, including cancer. SASP factors can be globally divided into the following major categories: soluble signaling factors (interleukins, chemokines, and growth factors), secreted proteases, and secreted insoluble proteins/extracellular matrix (ECM) components. SASP proteases can have three major effects: (a) shedding of membrane-associated proteins, resulting in soluble versions of membrane-bound receptors, (b) cleavage/degradation of signaling molecules, and/or (c) degradation or processing of the ECM. These activities provide potent mechanisms by which senescent cells can modify the tissue microenvironment. In the following sections, we discuss these SASP subsets and some of their known paracrine effects on nearby cells, with an emphasis on their ability to facilitate cancer progression.
Overall, senescence is a molecular program with a unique phenotypic outcome. How its extracellular molecular signature is activated and maintained and the extent to which it influences the tissue milieu in healthy tissues, aged tissues, and diseased tissues are some of the many questions that remain unanswered. However, even with our currently limited knowledge of the SASP and its potential effects on carcinogenesis, promising new strategies for cancer therapies are possible. For example, restoring the activity of tumor-suppressor proteins is an attractive, potentially powerful therapeutic approach. Taking into account our present understanding of the cell-nonautonomous effects of tumor-suppressor genes such as p53, small chemicals that can pharmacologically restore their normal function would help reestablish the proper tissue and cell signals, thereby stimulating cancer regression (147–150). Such approaches could stimulate cancer elimination for two reasons: First, they would limit inflammation and thus possibly allow proper tissue repair; second, they would directly promote the immune-mediated clearance of cells that drive cancer progression.
Senescence-associated secretory phenotype
Senescence-associated secretory phenotype (SASP) is a phenotype associated with senescent cells wherein those cells secrete high levels of inflammatory cytokines, immune modulators, growth factors, and proteases.[1][2] SASP is one of the three main features of senescent cells, the other two features being arrested cell growth, and resistance to apoptosis.[3]
The concept and abbreviation of SASP originated with Judith Campisi, who first published on the subject in 2008.[1]
SASP expression is induced by a number of transcription factors, the most important of which is NF-κB.[4] SASP factors induce insulin resistance.[5]
SASP disrupts normal tissue function by producing chronic inflammation, induction of fibrosis and inhibition of stem cells.[6] Chronic inflammation associated with aging has been termed inflammaging, although SASP may be only one of the possible causes of that condition.[7] SASP factors stimulate the immune system to eliminate senescent cells.[8]
SASP factors from senescent cells reduce nicotinamide adenine dinucleotide in non-senescent cells,[9] thereby reducing the capacity for DNA repair and sirtuin activity in the non-senescent cells.[10]
Despite the fact that cellular senescence probably evolved as means of protecting against cancer early in life, SASP promotes the development of late-life cancers.[6][4] Cancer invasiveness is promoted primarily though the actions of the SASP factors interleukin 6 (IL-6) and interleukin 8 (IL-8).[1] In fact, SASP from senescent cells is associated with many aging-associated diseases, including not only cancer, but atherosclerosis and osteoarthritis.[2] For this reason, senolytic therapy has been proposed as a generalized treatment for these and many other diseases.[2]
SASP can also play a beneficial role, however, by promoting wound healing.[11] But in contrast to the persistent character of SASP in chronic inflammation, beneficial SASP in wound healing is transitory.[11] -Wiki
IN SHORT: SASP IS VERY BAD; IT POISONS YOUR SYSTEM WITH TOXIC INFLAMMATORY CYTOKINES FROM ZOMBIE SENESCENT CELLS AND PREMATURELY AGES YOU. THE SASP MUST GO!
THE KEY TO ELIMINATING ZOMBIE SENESCENT CELLS CONSISTS OF TWO PARTS:
- DOWN-REGULATING ANT-APOPTOTIC PATHWAYS THAT PROTECT THEM
- UP-REGULATING PRO-APOPTOTIC PATHWAYS THAT CAN KILL THEM
WHICH PATHWAYS?
HERE’S AN EXAMPLE OF SOME OF THEM:
ATTENTION: THIS IS VERY IMPORTANT TO UNDERSTAND IF YOU WANT TO BECOME A ZOMBIE KILLING MACHINE!
INSULIN IS ANTI-APOPTOTIC
WHICH MEANS IT
PROTECTS ZOMBIE CELLS FROM APOPTOSIS.
THIS IS WHY YOU CAN’T KILL THAT STUBBORN FAT NO MATTER WHAT YOU SEEM TO DO. INSULIN IS BLOCKING YOU FROM doing so.
- FOR MAXIMUM BENEFIT IT IS ADVISED A BLACK COFFEE FAST (NO CALORIES / NO INSULIN) WITH ZOMBIE CELL KILLER FOR A 3-7 DAY DURATION; THE LONGER THE BETTER! IN THE PRESENCE OF INSULIN THE BLEND NEEDS TO WORK THAT MUCH HARDER SO WHEN YOU DO EAT KEEP IT LOW INSULIN; PALEO KETOGENIC DIET IS BEST.
