New research revealed that the single biggest determinant of anxiety and depression was traumatic life events, followed by to a lesser extent, family history of mental illness, income and education…
All about PTSD, honoring our veterans
- New research revealed that the single biggest determinant of anxiety and depression was traumatic life events, followed by to a lesser extent, family history of mental illness, income and education levels, relationship status and other social factors
- The study also found the way you think about traumatic life events directly affects your mental health
- Researchers have also determined that an alteration in the Brain Derived Neurotrophic Factor (BDNF) gene may further contribute to the risk of anxiety, depression and memory loss
- Growing evidence indicates that exercise trigger genes and growth factors like BDNF that recycle and rejuvenate your brain tissues; exercise is also an effective treatment for depression
PTSD
Genetics play some role in the development of PTSD. Approximately 30% of the variance in PTSD is caused from genetics alone. For twin pairs exposed to combat in Vietnam, having a monozygotic (identical) twin with PTSD was associated with an increased risk of the co-twin’s having PTSD compared to twins that were dizygotic (non-identical twins).[1] There is also evidence that those with a genetically smaller hippocampus are more likely to develop PTSD following a traumatic event. Research has also found that PTSD shares many genetic influences common to other psychiatric disorders. Panic and generalized anxiety disorders and PTSD share 60% of the same genetic variance. Alcohol, nicotine, and drug dependenceshare greater than 40% genetic similarities.[2]
Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain. A recent study reported significant interactions between three polymorphisms in the GABA alpha-2 receptor gene and the severity of childhood trauma in predicting PTSD in adults. A study found those with a specific genotype for G-protein signaling 2 (RGS2), a protein that decreases G protein-coupled receptor signaling, and high environmental stress exposure as adults and a diagnosis of lifetime PTSD. This was particularly prevalent in adults with prior trauma exposure and low social support.[2]
Recently, it has been found that several single-nucleotide polymorphisms (SNPs) in FK506 binding protein 5 (FKBP5) interact with childhood trauma to predict severity of adult PTSD.[3][4] These findings suggest that individuals with these SNPs who are abused as children are more susceptible to PTSD as adults.
This is particularly interesting given that FKBP5 SNPs have previously been associated with peritraumatic dissociation in medically injured children (that is, dissociation at the time of the birth trauma),[5] which has itself been shown to be predictive of PTSD.[6][7] Furthermore, FKBP5 may be less expressed in those with current PTSD.[8] Another recent study found a single SNP in a putative estrogen response element on ADCYAP1R1 (encodes pituitary adenylate cyclase-activating polypeptide type I receptor or PAC1) to predict PTSD diagnosis and symptoms in females.[9] Incidentally, this SNP is also associated with fear discrimination. The study suggests that perturbations in the PACAP-PAC1 pathway are involved in abnormal stress responses underlying PTSD.
PTSD is a psychiatric disorder that requires an environmental event that individuals may have varied responses to so gene-environment studies tend to be the most indicative of their effect on the probability of PTSD then studies of the main effect of the gene. Recent studies have demonstrated the interaction between PFBP5 and childhood environment to predict the severity of PTSD. Polymorphisms in FKBP5 have been associated with peritraumatic dissociation in mentally ill children. A study of highly traumatized African-American subjects from inner city primary-care clinics indicated 4 polymorphisms of the FKBP5 gene, each of these functional. The interaction between the polymorphisms and the severity of childhood abuse predicts the severity of the adult PTSD symptoms.
20 Percent of Population May Have a Gene Variant Linked to Depression
Brain Derived Neurotrophic Factor (BDNF), is a key growth hormone that promotes healthy brain neurons and plays a vital role in memory. BDNF levels are critically low in people with depression, which animal models suggest may actually be a primary contributing cause.
Now researchers have determined that an alteration known as a single nucleotide polymorphism (SNP) in the BDNF gene may further contribute to the risk of anxiety, depression and memory loss. All it takes is for one ‘letter’ of BDNF’s genetic code to be ‘misspelled’ for the alteration to occur.
The SNP alteration not only decreases BDNF in neurons but also generates a protein (called Met66) that is different from the one produced by people without the alteration.
About 20 percent of the US population is thought to have the BDNF SNP that produces the Met66 protein, which, in turn, has been found to induce shrinking of neurons in the hippocampus, in areas of the brain important for memory and emotions. The shrinkage would reduce the connectivity between brain cells.
One of the study’s researchers noted:5
“There can be a heritable component to these diseases and it makes sense that a common variant in a gene could be involved … Just like hypertension contributes to the risk for heart disease, the BDNF alteration increases the risk of depression, anxiety and memory disorders — but is not the sole reason why they occur.”
The researchers are currently looking to develop drugs that would target Met66 or block the proteins it binds to in people with the BDNF SNP alteration. However, it would be interesting to see how natural methods that promote optimal genetic expression would work instead.
Growing evidence indicates that both fasting and exercise trigger the expression of genes and growth factors that recycle and rejuvenate your brain tissues. These growth factors include BDNF, which is known to be released in response to the stress of exercise.
Getting back to the original study that found traumatic life events are the major determining factor in depression and anxiety – but that the way you think about them is an equally strong determining factor, let’s discuss how you can overcome such an emotional hurdle. The Emotional Freedom Techniques (EFT) is a form of psychological acupressure based on the same energy meridians used in traditional acupuncture to treat physical and emotional ailments for over 5,000 years, but without the invasiveness of needles.
Instead, simple tapping with the fingertips is used to transfer kinetic energy onto specific meridians on your head and chest while you think about your specific problem — whether it is a traumatic event, an addiction, pain, anxiety, etc. — and voice positive affirmations. This combination of tapping the energy meridians and voicing positive affirmation works to clear the “short-circuit”—the emotional block—from your body’s bioenergy system, thus restoring your mind and body’s balance, which is essential for optimal health and the healing of physical and mental disease.
Some people are initially wary of these principles that EFT is based on — the electromagnetic energy that flows through the body and regulates our health is only recently becoming recognized by western medicine. Others are initially taken aback by (and sometimes amused by) the EFT tapping and affirmation methodology.
But believe me when I say that, more than any traditional or alternative method I have used or researched, energy psychology (EFT being one type) has the most potential to literally work magic in this area. Clinical trials have shown that EFT is able to rapidly reduce the emotional impact of memories and incidents that trigger emotional distress. Once the distress is reduced or removed, the body can often rebalance itself, and accelerate healing. In the video above, EFT practitioner Julie Schiffman shows how you can use EFT to even get rid of panic attacks.
The Gut Connection to Anxiety and Depression
Another factor worth mentioning is that unhealthy gut flora can impact your mental health, leading to issues such as anxiety, depression, autism and more. Research has found, for instance, that the probiotic Lactobacillus rhamnosus had a marked effect on GABA [an inhibitory neurotransmitter that is significantly involved in regulating many physiological and psychological processes] levels in certain brain regions and lowered the stress-induced hormone corticosterone, resulting in reduced anxiety- and depression-related behavior.7
Interestingly, just as you have neurons in your brain, you also have neurons in your gut, including neurons that produce neurotransmitters like serotonin, which is also found in your brain. In fact, the greatest concentration of serotonin, which is involved in mood control, is found in your intestines, not your brain! (Perhaps this is another reason why antidepressants, which raise serotonin levels in your brain, are often ineffective in treating depression, whereas proper dietary changes often help.) This is where dietary changes such as reducing sugar intake and increasing your intake of probiotic-rich fermented foods can be invaluable for mood support.
Six Additional Factors for Improving Your Mental Health
There’s no doubt in my mind that addressing traumatic life events is a crucial step to prevent and/or address depression and anxiety. That said, here are six additional strategies that can help you even further:
- Exercise – If you have depression, or even if you just feel down from time to time, exercise is a MUST. The research is overwhelmingly positive in this area, with studies confirming that physical exercise is at least as good as antidepressants for helping people who are depressed. One of the primary ways it does this is by increasing the level of endorphins, the “feel good” hormones, in your brain. It also helps to normalize your insulin and leptin signaling.
- Eat a healthy diet – A factor that cannot be overlooked is your diet. Foods have an immense impact on your mood and ability to cope and be happy, and eating whole foods as described in my nutrition plan will best support your mental health. Avoiding sugar and grains will help normalize your insulin and leptin levels, and eliminating artificial sweeteners will eliminate your chances of suffering its toxic effects.
- Optimize your gut health – Fermented foods, such as fermented vegetables are also important for optimal mental health, as they are key for optimizing your gut health. Many fail to realize that your gut is literally your second brain, and can significantly influence your mind, mood, and behavior. Your gut actually produces more mood-boosting serotonin than your brain does.
- Support optimal brain functioning with essential fats – I also strongly recommend supplementing your diet with a high-quality, animal-based omega-3 fat, like krill oil. This may be the single most important nutrient to battle depression.
- Get plenty of sunshine – Making sure you’re getting enough sunlight exposure to have healthy vitamin D levels is also a crucial factor in treating depression or keeping it at bay. One previous study found that people with the lowest levels of vitamin D were 11 times more prone to be depressed than those who had normal levels. Vitamin D deficiency is actually more the norm than the exception, and has previously been implicated in both psychiatric and neurological disorders.
- Address your stress – Depression is a very serious condition, however it is not a “disease.” Rather, it’s a sign that your body and your life are out of balance. This is so important to remember, because as soon as you start to view depression as an “illness,” you think you need to take a drug to fix it. In reality, all you need to do is return balance to your life, and one of the key ways to doing this is addressing stress. Meditation or yoga can sometimes help. If weather permits, get outside for a walk. But in addition to that you can also use EFT, as mentioned.
Know if cancer will strike your body years from now
If you know from genetic tests that cancer will develop in 20yrs, would you like to know that to give you time to fight cancer? If you get a prognostic biomarker tests to measure your molecular age…
Know if cancer will strike your body years from now
If you know from genetic tests that cancer will develop in 20yrs, would you like to know that to give you time to fight cancer?
If you get a prognostic biomarker tests to measure your molecular age so that you have time to slow aging, would you be interested in that?
Would you like a complete DNA sequence tests to know majority of the genes that are essential in making you healthy?
Soon, at http://www.avatarcare.net site, we can bring this predictive medicine with your participation where we can gather more health data to create actionable health points to help find cure for cancer or slow the aging process. Email motherhealth@gmail.com if you wanted this health concierge site and help it develop to serve more people.
The site will also let you find doctors, hospital staff, specialists and caregivers. You can have a video chat with your doctor and set up an electronic schedule with your doctor.
Doctors and health consumers can communicate early before an emergency happens. We can all participate in our own health.
For example, if we gather more health data, such as below, we can create analytics.
Share this with your doctor, together we can effect health and collaborate with every one in the care time. We will help doctors facilitate information delivery and provide communication link and more.
mRNA molecules, oxidative damage in the heart, stress response and longevity
Gene expression profile was obtained with high-density oligonucleotide microarrays. Of 9,977 genes represented on the microarray, 249 transcripts in the young mice, 298 transcripts in the middle-ag…
Source: mRNA molecules, oxidative damage in the heart, stress response and longevity
mRNA molecules, oxidative damage in the heart, stress response and longevity
Gene expression profile was obtained with high-density oligonucleotide microarrays. Of 9,977 genes represented on the microarray, 249 transcripts in the young mice, 298 transcripts in the middle-aged mice, and 256 transcripts in the old mice displayed a significant change in mRNA levels (ANOVA, P < 0.01).
Among these, a total of 55 transcripts were determined to be paraquat responsive for all age groups. Genes commonly induced in all age groups include those associated with stress, inflammatory, immune, and growth factor responses. Interestingly, only young mice displayed a significant increase in expression of all three isoforms of GADD45, a DNA damage-responsive gene.
Additionally, the number of immediate early response genes (IEGs) found to be induced by paraquat was considerably higher in the younger animals. These results demonstrate that, at the transcriptional level, there is an age-related impairment of specific inducible pathways in the response to oxidative stress in the mouse heart.
Although the increased susceptibility of older animals to various forms of stress has been well documented, little is known about the genetic basis underlying this change (31, 37). There is also evidence to suggest that longevity and the ability to resist oxidative and metabolic stress are related processes. Several long-lived mutants have been identified in Saccharomyces cerevisiae (13), Drosophila (27), and Caenorhabditis elegans (35) that exhibit increased resistance to a wide range of physiological and pharmacological insults.
The basic molecular defense systems employed by these organisms are very similar to those utilized in mammals (40, 52), suggesting that stress responses may also play a role in aging of longer lived species. In mammals, the only intervention that is proven to extend lifespan is caloric restriction (CR) (53), and CR rodents display increased resistance to heat shock (18, 21) and oxidative damage (45).
The endogenous production of reactive oxygen species (ROS), a by-product of cellular respiration, may contribute to the aging phenotype (19). The heart is an organ that is likely to be particularly vulnerable to increases in oxidative stress, since cardiomyocytes depend heavily on mitochondrial function. The ability to cope with cardiovascular injury has been shown to decline with age (23, 29, 30), and many heart-related stresses, such as myocardial ischemia and reperfusion, generate ROS that may contribute to pathology (11). Possibly, the age-associated increase in the production of ROS contributes to the observed decline in the ability to recover from cardiac-related trauma in the aged animal (23, 29, 30).
Previous studies using high-density oligonucleotide arrays have characterized the basal transcriptional response to the aging process in skeletal muscle (25), brain (26), and heart (24) of mice. However, this technology has not been used to characterize the transcriptional response to acute oxidative stress as a function of age.
Accordingly, we investigated the transcriptional response to oxidative damage in the heart by challenging 5-mo-old (young), 15-mo-old (middle-aged), and 25-mo-old mice with paraquat. Paraquat is a toxin that reacts with molecular oxygen in vivo to generate ROS in several tissues and has been used previously to elicit oxidative stress in rodents (2, 10, 50). Paraquat ingestion in rats and humans leads to severe heart damage (36, 39) and an increase in the levels of 8-hydroxydeoxyguanosine in the heart, a marker of oxidative DNA damage (48).
About mRNA
Messenger RNA (mRNA) is a large family of RNA molecules that convey genetic information from DNA to the ribosome, where they specify the amino acid sequence of the protein products of gene expression. Following transcription of primary transcript mRNA (known as pre-mRNA) by RNA polymerase, processed, mature mRNA is translated into a polymer of amino acids: a protein, as summarized in the central dogma of molecular biology.
As in DNA, mRNA genetic information is in the sequence of nucleotides, which are arranged into codons consisting of three base pairs each. Each codon encodes for a specific amino acid, except the stop codons, which terminate protein synthesis. This process of translation of codons into amino acids requires two other types of RNA: Transfer RNA (tRNA), that mediates recognition of the codon and provides the corresponding amino acid, and ribosomal RNA (rRNA), that is the central component of the ribosome’s protein-manufacturing machinery.
Oxidative stress and metal catalysts in depression, aging and cancer
In humans, oxidative stress is thought to be involved in the development of Asperger syndrome,[2] ADHD,[3]cancer,[4] Parkinson’s disease,[5] Lafora disease,[6]Alzheimer’s disease,[7] at…
Source: Oxidative stress and metal catalysts in depression, aging and cancer
Oxidative stress and metal catalysts in depression, aging and cancer
Reactive oxygen species (ROS), byproducts of oxygen metabolism, are present in the cells as a consequence of living in an oxygen-rich atmosphere. ROS can be generated by both endogenous and exogenous sources, such as mitochondria and carcinogens, respectively.
ROS contain superoxide (O2•−) and hydrogen peroxide (H2O2), and are important for the normal function of many cellular processes, including metabolism, cell growth and differentiation, immune responses and apoptosis.
Low levels of ROS serve as secondary messengers and are essential for carrying out these cellular functions.
Overproduction of ROS and generation of highly reactive ROS, for example hydroxyl (•OH) radicals, can attack lipids, protein, DNA, and other cellular components, leading to numerous diseases, among them cancer, and cardiovascular and neurological disorders.
In humans, oxidative stress is thought to be involved in the development of Asperger syndrome,[2] ADHD,[3]cancer,[4] Parkinson’s disease,[5] Lafora disease,[6]Alzheimer’s disease,[7] atherosclerosis,[8] heart failure,[9]myocardial infarction,[10][11] fragile X syndrome,[12]Sickle Cell Disease,[13] lichen planus,[14] vitiligo,[15]autism,[16] infection, Chronic fatigue syndrome,[17] and Depression.[18] However, reactive oxygen species can be beneficial, as they are used by the immune system as a way to attack and kill pathogens.[19] Short-term oxidative stress may also be important in prevention of aging by induction of a process named mitohormesis.
Exposure to genotoxic agents in the environment such as ionizing radiation, UV, and chemical carcinogens leads to DNA damage. Additionally, some endogenous agents derived from cellular metabolism such as reactive oxygen species (ROS) also frequently damage DNA. DNA damage is cytotoxic and genotoxic, which can result in acute cell killing or prolonged deleterious biological effects that include chromosomal aberrations, gene mutations, cancer, neurodegeneration, and aging. Cells contain complex systems in response to DNA damage.
Metal catalysts
Metals such as iron, copper, chromium, vanadium, and cobalt are capable of redox cycling in which a single electron may be accepted or donated by the metal. This action catalyzes production of reactive radicals and reactive oxygen species.[68] The presence of such metals in biological systems in an uncomplexed form (not in a protein or other protective metal complex) can significantly increase the level of oxidative stress. These metals are thought to induce Fenton reactions and the Haber-Weiss reaction, in which hydroxyl radical is generated from hydrogen peroxide. The hydroxyl radical then can modify amino acids. For example, meta-tyrosine and ortho-tyrosine form by hydroxylation of phenylalanine. Other reactions include lipid peroxidation and oxidation of nucleobases. Metal catalyzed oxidations also lead to irreversible modification of R (Arg), K (Lys), P (Pro) and T (Thr) Excessive oxidative-damage leads to protein degradation or aggregation.[69]
The reaction of transition metals with proteins oxidated by Reactive Oxygen Species or Reactive Nitrogen Species can yield reactive products that accumulate and contribute to aging and disease. For example, in Alzheimer’s patients, peroxidized lipids and proteins accumulate in lysosomes of the brain cells.
Production of reactive oxygen species is a particularly destructive aspect of oxidative stress. Such species include free radicals and peroxides. Some of the less reactive of these species (such as superoxide) can be converted by oxidoreduction reactions with transition metals or other redox cycling compounds (including quinones) into more aggressive radical species that can cause extensive cellular damage.[23] Most long-term effects are caused by damage to DNA.[24] DNA damage induced by ionizing radiation is similar to oxidative stress, and these lesions have been implicated in aging and cancer. Biological effects of single-base damage by radiation or oxidation, such as 8-oxoguanine and thymine glycol, have been extensively studied. Recently the focus has shifted to some of the more complex lesions. Tandem DNA lesions are formed at substantial frequency by ionizing radiation and metal-catalyzed H2O2 reactions. Under anoxic conditions, the predominant double-base lesion is a species in which C8 of guanine is linked to the 5-methyl group of an adjacent 3′-thymine (G[8,5- Me]T).[25] Most of these oxygen-derived species are produced at a low level by normal aerobic metabolism. Normal cellular defense mechanisms destroy most of these. Likewise, any damage to cells is constantly repaired. However, under the severe levels of oxidative stress that cause necrosis, the damage causes ATP depletion, preventing controlled apoptotic death and causing the cell to simply fall apart.[26][27]
Polyunsaturated fatty acids, particularly arachidonic acid and linoleic acid, are primary targets for free radical and singlet oxygen oxidations.
The best studied cellular antioxidants are the enzymes superoxide dismutase (SOD), catalase, and glutathione peroxidase. Less well studied (but probably just as important) enzymatic antioxidants are the peroxiredoxins and the recently discovered sulfiredoxin. Other enzymes that have antioxidant properties (though this is not their primary role) include paraoxonase, glutathione-S transferases, and aldehyde dehydrogenases.
The amino acid methionine is prone to oxidation, but oxidized methionine can be reversible. Oxidation of methionine is shown to inhibit the phosphorylation of adjacent Ser/Thr/Tyr sites in proteins.[44] This gives a plausible mechanism for cells to couple oxidative stress signals with cellular mainstream signaling such as phosphorylation.
Copper, Iron and Ionizing radiation causing DNA damage
Hydrogen peroxide is an important reactive oxygen species (ROS) that arises either during the aerobic respiration process or as a by-product of water radiolysis after exposure to ionizing radiation.
The reaction of hydrogen peroxide with transition metals imposes on cells an oxidative stress condition that can result in damage to cell components such as proteins, lipids and principally to DNA, leading to mutagenesis and cell death.
Escherichia colicells are able to deal with these adverse events via DNA repair mechanisms, which enable them to recover their genome integrity. These include base excision repair (BER), nucleotide excision repair (NER) and recombinational repair.
Other important defense mechanisms present in Escherichia coli are OxyR and SosRS anti-oxidant inducible pathways, which are elicited by cells to avoid the introduction of oxidative lesions by hydrogen peroxide.
This review summarizes the phenomena of lethal synergism between UV irradiation (254 nm) and H2O2, the cross-adaptive response between different classes of genotoxic agents and hydrogen peroxide, and the role of copper ions in the lethal response to H2O2 under low-iron conditions.
http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1415-47572004000200026
Copper and Hydrogen Peroxide
Oxidative DNA damage may play an important role in human disease including cancer.
Previously, mutational spectra have been determined using systems that include transition metal ions and hydrogen peroxide (H2O2).
G→T transversions and C→T transitions were the most common mutations observed including some CC→TT tandem mutations. C→T transition mutations at methylated CpG dinucleotides are the most common mutations in human genetic diseases. It has been hypothesized that oxidative stress may increase the frequency of mutations at methylated CpG sequences. Here we have used a CpG-methylated shuttle vector to derive mutational spectra of copper/H2O2-induced DNA damage upon passage of the shuttle vector through human fibroblasts.
We find that copper/H2O2 treatment produces higher numbers of CpG transition mutations when the CpGs are methylated but does not create clear C→T hotspots at these sites.
More strikingly, we observed that this treatment produces a substantial frequency of mutations that were mCG→TT tandem mutations. Six of seven tandem mutations were of this type. mCG→TT mutations (6/63 = 10% of all mutations) were observed only in nucleotide excision repair-deficient (XP-A) cells but were not found in repair-proficient cells.
The data suggest that this novel type of mutation may be produced by vicinal or cross-linked base damage involving 5-methylcytosine and a neighboring guanine, which is repaired by nucleotide excision repair. We suggest that the underlying oxidative lesions could be responsible for the progressive neurodegeneration seen in XP-A individuals.
DNA damage induced by reactive oxygen species (ROS) is an important intermediate in the pathogenesis of human conditions such as cancer and aging (1–5).
ROS-induced DNA damage products are both mutagenic and cytotoxic.
Hydrogen peroxide (H2O2), which generates hydroxy radicals in the presence of transition metal ions, is considered an appropriate model for ROS.
H2O2 is produced endogenously by several physiological processes, e.g. during oxidative phosphorylation (6) and by the inflammatory cell respiratory burst (7).
Because it is freely diffusible, H2O2 can potentially reach the nucleus to interact with DNA (8). H2O2 causes strand breaks (9) and base damage (10,11) in DNA by a mechanism that requires transition metal ions, such as iron or copper (12–14). Mixtures of Cu(II) ions and H2O2, often with added ascorbic acid, produce extensive strand breaks in DNA (15–17). Strand breaks often occur near guanine residues, and it has been suggested that copper ions bind to DNA at these sites (15). Indeed, Cu(II)-dependent DNA fragmentation has been reported to be much more extensive than that produced by equimolar Fe(III) ions in comparable reaction mixtures (16,18,19). Cu(II)/ascorbate/H2O2-mediated DNA damage in aerobic aqueous solutions is believed to be induced in vitro and in vivo through formation of a DNA–Cu(I)–H2O2 complex (16,20–22). DNA damage induced by copper/H2O2 is enhanced by packaging of DNA into nucleosomes (23).
Exposure of target cells to H2O2 reproduces at least some components of the known endogenous DNA damage spectrum.
More than 30 different sugar and base modifications have been identified (11). Levels of oxidative DNA damage products have been measured in tissues by a variety of techniques and, although there is some controversy about the ‘true’ level of oxidative DNA damage, the levels can be quite substantial (24,25).
It is unclear which of the many different lesions produced by DNA oxidation is the one most responsible for inducing mutations. The mutations that are produced depend on the source of the ROS and the particular experimental system used to study the mutations.
Tumor protein p53 activated by DNA damage- UV and oxidative stress
Tumor protein p53, also known as p53, cellular tumor antigen p53(UniProt name), phosphoprotein p53, tumor suppressor p53, antigen NY-CO-13, or transformation-related protein 53 (TRP53), is any isoform of a protein encoded by homologous genes in various organisms, such as TP53 (humans) and Trp53 (mice).
This homolog (originally thought to be, and often spoken of as, a single protein) is crucial in multicellular organisms, where it prevents cancer formation, thus, functions as a tumor suppressor.[4]
As such, p53 has been described as “the guardian of the genome” because of its role in conserving stability by preventing genome mutation.[5] Hence TP53 is classified as a tumor suppressor gene.[6][7][8][9][10] (Italics are used to denote the TP53 gene name and distinguish it from the protein it encodes.)
p53 becomes activated in response to myriad stressors, including but not limited to DNA damage (induced by either UV, IR, or chemical agents such as hydrogen peroxide), oxidative stress,[41] osmotic shock, ribonucleotide depletion, and deregulated oncogene expression. This activation is marked by two major events. First, the half-life of the p53 protein is increased drastically, leading to a quick accumulation of p53 in stressed cells. Second, a conformational change forces p53 to be activated as a transcription regulator in these cells. The critical event leading to the activation of p53 is the phosphorylation of its N-terminal domain. The N-terminal transcriptional activation domain contains a large number of phosphorylation sites and can be considered as the primary target for protein kinases transducing stress signals.
The protein kinases that are known to target this transcriptional activation domain of p53 can be roughly divided into two groups. A first group of protein kinases belongs to the MAPK family (JNK1-3, ERK1-2, p38 MAPK), which is known to respond to several types of stress, such as membrane damage, oxidative stress, osmotic shock, heat shock, etc. A second group of protein kinases (ATR, ATM, CHK1 and CHK2, DNA-PK, CAK, TP53RK) is implicated in the genome integrity checkpoint, a molecular cascade that detects and responds to several forms of DNA damage caused by genotoxic stress. Oncogenes also stimulate p53 activation, mediated by the protein p14ARF.
In unstressed cells, p53 levels are kept low through a continuous degradation of p53. A protein called Mdm2 (also called HDM2 in humans), binds to p53, preventing its action and transports it from the nucleus to the cytosol. Also Mdm2 acts as ubiquitin ligase and covalently attaches ubiquitin to p53 and thus marks p53 for degradation by the proteasome. However, ubiquitylation of p53 is reversible.
The novel molecule MI-63 binds to MDM2 making the action of p53 again possible in situations were p53’s function has become inhibited.[42]
A ubiquitin specific protease, USP7 (or HAUSP), can cleave ubiquitin off p53, thereby protecting it from proteasome-dependent degradation via the ubiquitin ligase pathway. This is one means by which p53 is stabilized in response to oncogenic insults. USP42 has also been shown to deubiquitinate p53 and may be required for the ability of p53 to respond to stress
Pursuing longevity: Epigenetic clock and cellular senescence
Epigenetic clock analysis of cellular senescence According to a molecular biomarker of aging known as epigenetic clock,[14] the three major types of cellular senescence, namely replicative senescen…
Source: Pursuing longevity: Epigenetic clock and cellular senescence
Pursuing longevity: Epigenetic clock and cellular senescence
Epigenetic clock analysis of cellular senescence
According to a molecular biomarker of aging known as epigenetic clock,[14] the three major types of cellular senescence, namely replicative senescence, oncogene-induced senescence and DNA damage-induced senescence are distinct because induction of replicative senescence (RS) and oncogene-induced senescence (OIS) were found to be accompanied by epigenetic aging of primary cells but senescence induced by DNA damage was not, even though RS and OIS activate the cellular DNA damage response pathway.[15] These results highlight the independence of cellular senescence from epigenetic aging. Consistent with this, telomerase-immortalised cells continued to age (according to the epigenetic clock) without having been treated with any senescence inducers or DNA-damaging agents, re-affirming the independence of the process of epigenetic ageing from telomeres, cellular senescence, and the DNA damage response pathway.
Although the uncoupling of senescence from cellular aging appears at first sight to be inconsistent with the fact that senescent cells contribute to the physical manifestation of organism ageing, as demonstrated by Baker et al., where removal of senescent cells slowed down aging .[10] However, the epigenetic clock analysis of senescence suggests that cellular senescence is a state that cells are forced into as a result of external pressures such as DNA damage, ectopic oncogene expression and exhaustive proliferation of cells to replenish those eliminated by external/environmental factors.[15] These senescent cells, in sufficient numbers, will undoubtedly cause the deterioration of tissues, which is interpreted as organism ageing. However, at the cellular level, aging, as measured by the epigenetic clock, is distinct from senescence. It is an intrinsic mechanism that exists from the birth of the cell and continues. This implies that if cells are not shunted into senescence by the external pressures described above, they would still continue to age. This is consistent with the fact that mice with naturally long telomeres still age and eventually die even though their telomere lengths are far longer than the critical limit, and they age prematurely when their telomeres are forcibly shortened, due to replicative senescence. Hence senescence is a route by which cells exit prematurely from the natural course of cellular ageing.[15]
Aging of the whole organism
Organismal senescence is the aging of whole organisms. In general, aging is characterized by the declining ability to respond to stress, increased homeostatic imbalance, and increased risk of aging-associated diseases. Death is the ultimate consequence of aging, though “old age” is not a scientifically recognized cause of death because there is always a specific proximal cause, such as cancer, heart disease, or liver failure. Aging of whole organisms is therefore a complex process that can be defined as “a progressive deterioration of physiological function, an intrinsic age-related process of loss of viability and increase in vulnerability.”[16]
Differences in maximum life span among species correspond to different “rates of aging.” For example, inherited differences in the rate of aging make a mouse elderly at 3 years and a human elderly at 80 years.[17] These genetic differences affect a variety of physiological processes, including the efficiency of DNA repair, antioxidant enzymes, and rates of free radicalproduction.
Supercentenarian Ann Pouder(8 April 1807 – 10 July 1917) photographed on her 110th birthday. A heavily lined face is common in human senescence.
Senescence of the organism gives rise to the Gompertz–Makeham law of mortality, which says that mortality rate accelerates rapidly with age.
Some animals, such as some reptiles and fish, age slowly (negligible senescence) and exhibit very long lifespans. Some even exhibit “negative senescence”, in which mortality falls with age, in disagreement with the Gompertz–Makeham “law”.[1]
Whether replicative senescence (Hayflick limit) plays a causative role in organismal aging is at present an active area of investigation.
The oft-quoted evolutionary theorist George Williams wrote, “It is remarkable that after a seemingly miraculous feat of morphogenesis, a complex metazoan should be unable to perform the much simpler task of merely maintaining what is already formed.”[18]
There is a current debate as to whether or not the pursuit of longevity and the postponement of senescence are cost-effective health care goals given finite health care resources. Because of the accumulated infirmities of old age, bioethicist Ezekiel Emanuel, opines that the pursuit of longevity via the compression of morbidity hypothesis is a “fantasy” and that human life is not worth living after age 75; longevity then should not be a goal of health care policy.[19]
This opinion has been refuted by neurosurgeon and medical ethicist Miguel Faria, who states that life can be worthwhile during old age, and that longevity should be pursued in association with the attainment of quality of life.[20] Faria claims that postponement of senescence as well as happiness and wisdom can be attained in old age in a large proportion of those who lead healthy lifestyles and remain intellectually active.
Cellular senescence
As noted above, senescence is not universal. It was once thought that senescence did not occur in single-celled organisms that reproduce through the process of cellular mitosis.[36] Recent investigation has unveiled a more complex picture. Single cells do accumulate age-related damage. On mitosis the debris is not evenly divided between the new cells. Instead it passes to one of the cells leaving the other cell pristine. With successive generations the cell population becomes a mosaic of cells with half ageless and the rest with varying degrees of senescence.[37]
Moreover, cellular senescence is not observed in several organisms, including perennial plants, sponges, corals, and lobsters. In those species where cellular senescence is observed, cells eventually become post-mitotic when they can no longer replicate themselves through the process of cellular mitosis; i.e., cells experience replicative senescence. How and why some cells become post-mitotic in some species has been the subject of much research and speculation, but (as noted above) it is sometimes suggested that cellular senescence evolved as a way to prevent the onset and spread of cancer. Somatic cells that have divided many times will have accumulated DNA mutations and would therefore be in danger of becoming cancerous if cell division continued. As such, it is becoming apparent that senescent cells undergo conversion to an immunogenic phenotype that enables them to be eliminated by the immune system.[38]
Lately, the role of telomeres in cellular senescence has aroused general interest, especially with a view to the possible genetically adverse effects of cloning. The successive shortening of the chromosomal telomeres with each cell cycle is also believed to limit the number of divisions of the cell, thus contributing to aging. There have, on the other hand, also been reports that cloning could alter the shortening of telomeres.
Some cells do not age and are, therefore, described as being “biologically immortal“. It is theorized by some that when it is discovered exactly what allows these cells, whether it be the result of telomere lengthening or not, to divide without limit that it will be possible to genetically alter other cells to have the same capability.
It is further theorized that it will eventually be possible to genetically engineer all cells in the human body to have this capability by employing gene therapy and, therefore, stop or reverse aging, effectively making the entire organism potentially immortal.
The length of the telomere strand has senescent effects; telomere shortening activates extensive alterations in alternative RNA splicing that produce senescent toxins such as progerin, which degrades the tissue and makes it more prone to failure.[39]
Cancer cells are usually immortal
In about 85% of tumors, this evasion of cellular senescence is the result of up-activation of their telomerase genes.[40] This simple observation suggests that reactivation of telomerase in healthy individuals could greatly increase their cancer risk.
Ned Sharpless and collaborators demonstrated the first in vivo link between p16-expressing senescent cells and lifespan.[41]They found delayed senescent cell accumulation in mice with mutations that extend lifespan, as well as in mice that had their lifespan extended by food restriction. Later, Jan van Deursen and Darren Baker in collaboration with Andre Terzic at the Mayo Clinic in Rochester, Minn., provided the first in vivo evidence for a causal link between cellular senescence and aging by preventing the accumulation of senescent cells in BubR1 progeroid mice.[42]
In the absence of senescent cells, the mice’s tissues showed a major improvement in the usual burden of age-related disorders.
They did not develop cataracts, avoided the usual wasting of muscle with age. They retained the fat layers in the skin that usually thin out with age and, in people, cause wrinkling. Jan van Deursen, James Kirkland, Tamara Tchkonia, Nathan LeBrasseur, and Darren Baker at the Mayo Clinic in Rochester, Minn., provided the first direct in vivo evidence that cellular senescence causes signs of aging by eliminating senescent cells from progeroid mice by introducing a drug-inducible suicide gene and then treating the mice with the drug to kill senescent cells selectively, as opposed to decreasing whole body p16.[10] Another Mayo study led by James Kirkland in collaboration with Scripps and other groups demonstrated that senolytics, drugs that target senescent cells, enhance cardiac function and improve vascular reactivity in old mice, alleviate gait disturbance caused by radiation in mice, and delay frailty, neurological dysfunction, and osteoporosis in progeroid mice.
Discovery of senolytic drugs was based on a hypothesis-driven approach: the investigators leveraged the observation that senescent cells are resistant to apoptosis to discover that pro-survival pathways are up-regulated in these cells. They demonstrated that these survival pathways are the “Achilles heel” of senescent cells using RNA interference approaches, including Bcl-2-, AKT-, p21-, and tyrosine kinase-related pathways. They then used drugs known to target the identified pathways and showed these drugs kill senescent cells by apoptosis in culture and decrease senescent cell burden in multiple tissues in vivo.
Importantly, these drugs had long term effects after a single dose, consistent with removal of senescent cells, rather than a temporary effect requiring continued presence of the drugs. This was the first study to show that clearing senescent cells enhances function in chronologically aged mice.
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Source: What is your molecular age? P16 protein can ID your molecular age
How not to get pregnant under Trump presidency
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