The process of aging is inevitable for all individuals, as a result the immune system undergoes age-associated alterations. This deterioration of the immune system lowers the body’s ability to fight infections and is termed immunosenescence1. Immunosenescence is characterized by inflammation, increased oxidative stress and other deleterious process. In response to local inflammatory stimuli, isolated lymphoid follicles (ILFS) are formed. It has been observed that ILF dysfunction, due to aging, leads to immunosenescence of the mucosal system2. Some changes to the innate and adaptive immune response will be further explored by discussing the effects of inflammation, oxidative stress, and cancer on the immune system3,4. Inflammation is a homeostatic mechanism that initially protects the host organism from wound or pathogenic invasion. Aberrant chronic systemic inflammation occurs in many unrelated, age-related diseases, which accelerate aging by inducing tissue damage leading to organ degeneration. Chronic low-grade inflammation, as observed in the elderly, is associated with neuropsychiatric symptoms5. Moreover, this same form of inflammation induces atherosclerosis, cancer, heart valve dysfunction, obesity, diabetes, congestive heart failure, digestive system diseases, and Alzheimer's disease6. Aging results in increase of inflammatory cytokines and C-reactive protein which are utilized to diagnose the level of age-related degeneration within a patient7. Reactive oxygen species (ROS) are chemically-reactive molecules containing oxygen8. Among some examples there are oxygen ions and peroxides8. Reactive oxygen species turn out to be very reactive mainly because of the presence of unpaired valence shell electrons. ROS form as a natural byproduct of the normal metabolism of oxygen during cellular respiration8. However, during times of environmental stress, like exposure to sun light or heat, ROS levels can increase dramatically and cause damage to cell structures9. This cumulates into a situation known as oxidative stress. ROS can damage DNA, RNA, and proteins, and contribute to the physiology of aging9. Under normal conditions, our body cells are able to withstand ROS damage with the help of protective enzymes. It is important to point out that the protective functions of these enzymes are not 100% efficient and decline with normal aging10. Cancer is more prominently a disease of the elderly with the average diagnostic age being only a little lower than 7011. This is due to many progressive factors, including oxidative stress, increased exposure to environmental carcinogens and more importantly an impaired immune system. The state known as immunesenescence refers to an aging immune system that is more susceptible to infection being deficient in its surveillance of cellular growth, possibly leading to cancer12. Increasing age has a corresponding reduction in naïve T-cells and a decrease in diversity of the T-cell receptor repertoire, which results in a decrease in response to the appearance of tumor new antigens. Furthermore, although memory T-cells increase with increasing age, their diversity as well as functional integrity decreases, contributing to the inability of an aged immune system to respond to re-infection and/or tumor relapse. Although this correlation has been proven in many studies, the specific mechanism by which immunosenescence impacts tumor progression has yet to be discovered11.
References
1. Alper S. Model systems to the rescue: The relationship between aging and innate immunity. Communicative & Integrative Biology. 2010; 3:5, 409-414.
2. McDonald KG, Leach MR, Huang C, et al. Aging impacts isolated lymphoid follicle development and function. Immune Ageing. 2011; 8(1):1.
3. Aw D, Silva A, Palmer D. Immunosenescence: emerging challenges for an ageing population. The Authors Journal compilation. 2006
4. Caruso C,Silvio B, Colonna-Romano G,et al. Mechanisms of immunosenescence. Immunity & Ageing. 2009; 6(10)
5. Capuron L, Schroecksnadel S, Féart C, et al. Chronic Low-Grade Inflammation in Elderly Persons Is Associated with Altered Tryptophan and Tyrosine Metabolism: Role in Neuropsychiatric Symptoms. Biol Psychiatry. 2011
6. Devaux B, Scholz D, Hirche A, et al. Upregulation of cell adhesion molecules and the presence of low grade inflammation in human chronic heart failure. Eur Heart J. 1997; 18(3):470-9.
7. Van der Meide, Schellekens H. Cytokines and the immune response. Biotherapy. 1996;8(3-4):243-9.
8. Abul K. Abbas & Andrew H. Litchman . Cellular and Molecular Immunology. 5th ed. Elsavier Saunders; 2005.
9. Parham P. The Immune System. 2nd ed.,
10. Lim J & Luderer U. Oxidative damage increases and antioxidant gene expression decreases with aging in the mouse ovary. Biology of Reproduction. 2010
11. Derhovanessian E, Solana R, Larbi A, Pawelec G. Immunity, ageing and cancer. Immunity & Ageing. 2008; 5 (11), 1-16.
12. Hakim F, Flomerfelt F, Boyiadzis M, et al. immunity and cancer. Current Opinion in Immunlogy. 2004; 16, 151-156.
ROS (Reactive Oxygen Species) in aging
The aging have an effect on the immune system components, called immunosenescence, affecting both the innate and adaptive response1. The oxidative stress is strongly associated with aging process, by the accumulation of damage between the cells, including these involved in the immune system2,3. The immunosenescence is related to the increase of cancer, chronic inflammatory diseases, and autoimmune disease among old persons. The oxidative damage increases with some environmental factors, pathologies, such as diabetes and cardiovascular disease, and repeated infections2,3. The imbalance between the overproduction of free radical during oxidative reactions and the reduce amount of antioxidants elucidate aging4. An application for the use of antioxidants has been done in diabetes mellitus patients. Glycation end products formed in patients with diabetes mellitus due to chronic hyperglycemia have been suggested to produce oxidative stress. The use of supplementation with vitamin E showed a protection in the cardiovascular epithelium among this patients5. A low calorie diet and an intake of nutrients such as antioxidants and vitamins are recommended to reduce or prevent the immunosenescence caused by oxidative stress5. Another therapy to reduce the effects of the ROS is the use of modified antioxidants. The approach is to target mitochondria to reduce mitochondrial oxidative damage that occurs in some pathology. Some effects that have been proved for those antioxidants are protection against cardiac and liver damage during a sepsis and to preserve the function of an organ for transplantation6. We naturally produce some enzymes with an activity antioxidant and have been proved that melatonin act on them. Melatonin, a hormone produced by the pineal gland, is associated with antioxidant activity detoxifying reactive oxygen species7. It acts on some enzymes, as superoxide dismutase and glutathione peroxidase, to upregulate its activity to help resist oxidative stress7. Some studies report that melatonin exert an anti-inflammatory activity reducing cytokines including IL-6, IL-8, and tumor necrosis factor involved in inflammatory response in some diseases7. Beside that the oxidative stress is a normal process that occurs in our body, we can reduce or prevent the overproduction of the ROS considering our life style.
References
1. Alper S. Model systems to the rescue: The relationship between aging and innate immunity. Communicative & Integrative Biology. 2010; 3:5, 409-414.
2. Pandey K, Ibrahim S. Markers of oxidative stress in erythrocytes and plasma during aging in humans. Oxidative Medicine and Cellular Longevity. 2010; 3:1, 2-12
3. Ongrádi J, Kövesdi V. Factors that may impact on immunosenescence:
an appraisal. Immunity & Ageing; 2010, 7:7
4. Pérez R. Update on the oxidative stress theory of aging: does oxidative stress play a role in aging or healthy aging? Free Radic Biol Med. 2010; 48(5):642-55
5. Karasu C. Glycoxidative Stress and Cardiovascular Complications in Experimentally-Induced Diabetes: Effects of Antioxidant Treatment. Open Cardiovascular Medicine Journal. 2010; 4, 240-256
6. Smith R, Murphy M. Mitochondria-targeted Antioxidants as Therapies. Article Published in the Author Account of Robin A. J. Smith. 2011
7. Esposito E, Cuzzocreal, S. Antiinflammatory Activity of Melatonin in Central Nervous System. Current Neuropharmacology. 2010; 228-242
A study demonstrated that out of 5,000 elderly people, frail seniors showed a higher likelihood of having signs of increased inflammation than their more active counterparts1. Moreover, the study showed that frail seniors had elevated blood inflammatory markers and exhibited greater clotting activity, muscle weakness, fatigue and disability than active elderly people. In Elderly patients with multiple degenerative diseases (atherosclerosis, cancer, heart valve dysfunction, obesity, diabetes, congestive heart failure, digestive system diseases, and Alzheimer's disease), the inflammatory marker, C-reactive protein, is elevated indicating the presence of inflammatory disorder2. Rheumatoid arthritis patients exhibit elevated levels of cytokines such as tumor necrosis factor-alpha (TNF-a), interleukin-6 (IL-6), interleukin-1)], and/or interleukin-8 (IL-8) are known to cause or contribute to the inflammatory syndrome3 .Cytokine blood profile conducted on weak patients deteriorating with organ failure typically results in an excess level of one or more of the inflammatory cytokines, e.g., C-reactive Protein, TNF-a, IL-6, IL-1(b), or IL-82. It is very interesting that a cytokine panel can reveal similar results within the elderly and thus inflammatory disorders such as Rheumatoid arthritis are commonly linked to aging disorders. Taken together, elderly patients should annually have their blood tested for C-reactive protein and inflammatory mediators (inflammatory cytokine test panel), as they get older, to determine if they have an elevated inflammatory response system. Those who suffer from any type of chronic disease may also consider the Inflammatory Cytokine Test Panel in order to identify if they are at risk for Rheumatoid arthritis2.
References
1. Watson DJ, Rhodes T, Cai B, et al. Lower risk of thromboembolic cardiovascular events with naproxen among patients with rheumatoid arthritis. Arch Intern Med. 2002;May 27;162(10):1105-10.
2. Santoro A & Mancini E. Cardiac effects of chronic inflammation in dialysis patients. Nephrol Dial Transplant. 2002; 17 Suppl 8:10-5.
3. Deon D, Ahmed S, Tai K, et al. Cross-talk between IL-1 and IL-6 signaling pathways in rheumatoid arthritis synovial fibroblasts. J Immunol. 2001; Nov 1;167(9):5395-403.
Cancer
Although various factors may be considered in the causes of the development of cancer, one recently investigated is immunosenescence. Many researchers and numerous laboratory findings support the hypothesis that some tumors are manipulated, and possibly even induced, as a consequence of aging, which leads to decreased functionality of the human immune system1. Significantly, reduced numbers of T lymphocytes is one of the major characteristics found in elderly people, thereby augmenting the propensity to infections and the development of cancer2. For example, colorectal cancer is one of the leading causes of death in elderly people over 65 years of age2. The Fas-mediated apoptosis pathway is a potent tool used by T lymphocytes, specifically cytotoxic T cells, to attack defective cells in the colon that could give rise to cancerous cells3. Therefore, they have a suppressive effect on these diseased cells, impeding the possible development of colorectal cancer. As the immune system in the elderly becomes deficient due to its continuous aging, the reduction seen in cytotoxic CD8 cells will be reflected in an increase in diseased cells in the colon that can give rise to carcinogenic cells3.
References
1. Malaguarnera L, Ferlito L, Di Mauro S, Imbesi RM, Scalia G, Malaguarnera M. Immunosenescence and cancer: a review. Department of Biomedical Sciences, Via Androne, 83,
2. Cioca D, Herndler D, Grubeck B. Immunosenescence and tumourigenesis in elderly. European Journal of Geriatrics. 2007; 9, 2
3.Liu K. Role of apoptosis resistance in immune evasion and metastasis in colorectal cancer. World Journal of Gastrointestinal Oncology. 2010; 2, 11
Questions: Immunology and Aging
How does aging affect the immune system’s inflammatory response?
Normally inflammation results from an infection or recognition of an antigen by the immune system. However with aging the immune system loses tolerance to self tissues due to an increase in hypersensitivity, these affects the regulation of inflammatory response which is related to many diseases such as rheumatoid arthritis1.
1. Tao LE, Vikas Bhushan, Neil Vasan. First Aid for the USMLE Step1. 20th. ed. The Mc Graw-Hill Companies; 2010:379
A 53 years old women arrives to a clinic complaining pain and deformation in joints, she also reports to suffer from fever and fatigue. A chest X- Ray presents inflammation in the pleura and in the pericardium, also anti CCP antibodies test is positive. Which condition is affecting this patient?
A.Rheumatoid Arthritis
B.Gout
C.Osteoarthritis
D.Osteoporosis
E.Osteopenia
The answer is A. This disease is characterized by pain and deformation in the synovial joints. These symptoms may be similar to the other diseases mention above, however the presence of the positive test to CCP antibodies demonstrates this disease as autoimmune, which is the case of Rheumatoid arthritis.
Which of the following corresponds to the tumor mechanism used to evade immune response? (each arrow corresponds to one of the following processes: 1.Cytokine production; 2. MHC expression; 3. Induction of immune cell apoptosis
A. ↑ ↓ ↔
B. ↑ ↓ ↑
C. ↓ ↑ ↓
D. ↓ ↔ ↑
The answer is B. Cytokines are molecules that are capable of turning on or off particular immune responses. For example, IL-2 works to activate cell-mediated immune response, meanwhile IL-10 works to suppress the same response. Many cancers have developed the use of such cytokines to insure their survival against host immune system. Several cancer-cell lines have been shown to secrete immunosuppressive cytokines such as TGF-B (Tumor Growth Factor Beta), IL-10 (Interlukin 10) and VEGF (vascular endothelial growth factor). Some functions of TGF-B include the inhibition of immune cell (thymocytes, B cells, monocytes and NK cells) proliferation and induction of apoptosis of said immune cells. Furthermore, TGF-B down-regulates IL-2 receptors on T-cells thereby preventing MHC class II antigen presentation, allowing the cancer to go undetected as a foreign object.
Reference:
http://www.brown.edu/Courses/Bio_160/Projects1999/cancer/imevstca.html#shed> retrieved on May 3rd, 2011
What main immune cells respond to cancerous cells (cells that have mutated or transformed)?
CD8+ Cytotoxic T-cells through the MHC antigen-recognition pathway and, if no MHC then, through NK cells.
Dr. Smith was recently studying the effects of a compound found to be highly reactive due to the presence of unpaired valence shell electrons. After analyzing its properties Dr. Smith found that the compound was capable of producing significant damage to cell structures. However, he found that the damage could be prevented in the presence of substances such as ascorbic acid (vitamin C), tocopherol (vitamin E), uric acid, and glutathione. Dr. Smith was probably studying which type of molecules?
A. Proteins that damage your DNA.
B. Oxygen Molecules that increase your respiration rate.
C. Chemically-reactive molecules containing oxygen.
D. Oxygen molecules that accumulate in cartilage.
E. Oxygen molecules that athletes use to improve their performance
The answer is C.
What precautions and lifestyle changes can you do to reduce oxidative stress in your body?
Avoiding the exposure to ultraviolet light and smoke cigarette can contribute to the reduction of oxidative stress1. Another way to reduce the oxidative stress is through antioxidants. Some of them are the vitamin K, vitamin C, and vitamin E, found in some vegetables and fruits2.
1. Parham P. The Immune System. 2nd ed.,
2. Karasu C. Glycoxidative Stress and Cardiovascular Complications in Experimentally-Induced Diabetes: Effects of Antioxidant Treatment. Open Cardiovascular Medicine Journal. 2010; 4, 240-256
Videos and Additional Online Material
Group # 3 ImmunoBlog Website:
http://www.paginacibernetica.com/immunoblog
Animation Links:
http://www.youtube.com/watch?v=KVyjmt10CH0&feature=player_embedded http://www.youtube.com/watch?v=LEpTTolebqo&feature=player_embedded
http://www.youtube.com/watch?v=RZhL7LDPk8w&feature=player_embedded
http://www.youtube.com/watch?v=Ue6Yym25NWc&feature=player_embedded
Q triste q cuando más ayuda necesitamos de nuestro sistema inmune es cuando más débil se encuentra. Supongo q así es la ley de vida de alguna manera nuestro sistema tiene q ayudarnos a morir. Y debilitándose a medida q envejecemos suena lógico
ResponderEliminarExiste alguna manera de disminuir la proteina C reactiva??? o alguna forma de disminuir las citoquinas que causan los sintomas de artritis reumatoide???
ResponderEliminarAlthough not as healthy as fruit, dark chocolate and coffee provide antioxidants. I could go for a little oxidative stress reduction right now.
ResponderEliminarVery interesting blog, especially the subject about oxidative stress in Diabetes Mellitus patients. Also, it seems that any modification of the immune system, leads to cancer, which proves the importance of the immune system to prevent any type of disease.
ResponderEliminarEl envejeciemiento y sus efectos en el sistema inmune es una tema que parece no tener mucha literatura. Sería bueno que la investigación médica se enfocara un poco más en la inmunosenescencia en pacientes.
ResponderEliminarThe public needs to be careful to start taking supplements that say have "anti-oxidant" properties. Aside from not being FDA approved, they may be active as described in their PILL form but once they pass through the GI system you may encounter that these species may actually break down to reactive species.
ResponderEliminarI really enjoyed the whole subject very integrated with the most relevant topics of immunology and aging. Most importantly i really like your adaptation of questions and how you provided very detailed explanations.
ResponderEliminarMe parece muy interesante como mientras pasa el tiempo y envejecemos todo sistema se va debilitando incluso el sistema inmune!! tal vez el sistema inmune es una pieza clave en el proceso de envejecimiento y mas investigaciones nos pueden ayudar a entender mejor el proceso y el desarrollo de enfermedades relacionadas a la vejes!!
ResponderEliminar@Carlos: I completely agree. Just like diet crazes people tend to go on supplement crazes and pump their bodies full of things they don't understand or under-research. I say stick to vitamin D and a multi-vitamin. (vitamin D is getting some very good research press, and as my late great uncle Nando (a.k.a. Dr. Moreno) would say about a daily multi-vitamin: "well, it can't hurt".
ResponderEliminarA pesar de que el debilitarnos con la edad es parte de la vida muchas personas no toman medidas preventivas que le pueden evitar el tener estas enfermedades.
ResponderEliminarA medida que envejecemos la memoria del sistema inmune se va alterando, comienza con la acumulacion de ciertos productos como ROS estos se asocian a inflamacion y dano en vasos sanguineos reflejando arterosclerosis y diabetes. Tambien nos hace mas propensos a la artritis y al cancer al no reconocer y eliminar ciertos celulas y anticuerpos que no puede identificar como extranas
ResponderEliminarIt's funny how studies like the ones summarized here become trends in our society. Many people change their diets temporarily because commercials tell them that antioxidants are good for them, yet they have no idea how many benefits they can really provide. The trend passes and people go back to their old ways. My mom was one of these people. I think it is our responsibility as future physicians to educate our patients about even the smallest details that could potentially prolong their lives, maybe then will they actually stick to these trends (at least the good ones).
ResponderEliminarLa relación entre oxidative stress y diversas condiciones son temas de constante estudio.
ResponderEliminarMuchas células de condiciones como Neimman Pick y CF tienen mecanismos en los que expresan pocas proteinas proapoptóticas que se activan en presencia de peróxido.
Oxidative stress and the effect it has on our bodies is a well known topic among scientists; but the fact that leading a healthier lifestyle and adding more antioxidants to our diets aids in the process of diminishing said effects should be explained more often to patients by physicians, mostly to the elderly, in the hopes that they may lead a healthier, perhaps longer life. This entry is a nice way to do just that.
ResponderEliminarOxidative stress as a result of metabolic free radicals induces aging, there is definitely a correlation with hyperglycemia and the IGF pathway. The most interesting thing is when the homeostatic mechanisms of inflammation break down. Aberrant inflammation, particularly in organs leads to massive organ damage, thus accelerating aging even amongst the elderly! That was a point I tried to convey here, not sure if it made the final print, but yes it definitely strongly supports a direct relationship between disruption of homeostasis within the immune system and aging. In the example of RA its disruption of immune homeostasis. In the example of general aging, its going to be immunosenescence. Its important to understand the power of the inflammatory response on exhibiting damage on itself.
ResponderEliminarNunca habia pensado que el sistema imune jugara un papel tan importante en nuestro envejecimiento. Definitivamente todo nuestro cuerpo y los procesos que se llevan a cabo en el estan coordinados con nuestro sistema immune. Que pasaria si envejecieramos y nuestro sistema immune fuera tan fuerte como cuando teniamos 25 a~os? Creo que seriamos muy desgraciados pues a quien le gustaria vivir 130 a~os en un cuerpo ya desgastado y debil. Recordemos que la mayoria de los envejecientes mueren de diabetes, artherosclerosis, cancer, etc, Que son enfermedades con altos componentes imunologicos!! Si nuestro sistema fuese capaz de combatir todas enfermedades quedariamos atrapados en un cuerpo debil. Asi que envejecer es una ventaja y El que nos creo sabia que nuestro sistema imune tenia que envejecer a la par con nostros.
ResponderEliminarPor eso a veces debemos preguntarnos si vale la pena vivir tantos años. Porque como podemos ver, cuál es el propósito de procurar tener vidas extensas si vamos a incrementar nuestra vulnerabilidad cuando lleguemos a cierto punto en donde todo deja de funcionar. Jajajaja, no quiero que parezca de ninguna manera un comentario depresivo, pero eso es lo que vino a mi mente. Lo que hay que promover es la investigación en cómo extender la vida sin tener un cuerpo totalmente debilitado que dependa de fármacos y por ende tenga repercusiones como lo es la resistencia a antibióticos.
ResponderEliminar