Human genetic enhancement

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Human_genetic_enhancement 

 

An illustration of viral vector-mediated gene transfer using an adenovirus as the vector.

Human genetic enhancement or human genetic engineering refers to human enhancement by means of a genetic modification. This could be done in order to cure diseases (gene therapy), prevent the possibility of getting a particular disease (similarly to vaccines), to improve athlete performance in sporting events (gene doping), or to change physical appearance, metabolism, and even improve physical capabilities and mental faculties such as memory and intelligence. These genetic enhancements may or may not be done in such a way that the change is heritable (which has raised concerns within the scientific community).

Gene therapy

Further information: Gene therapy

Genetic modification in order to cure genetic diseases is referred to as gene therapy. Many such gene therapies are available, made it through all phases of clinical research and are approved by the FDA. Between 1989 and December 2018, over 2,900 clinical trials were conducted, with more than half of them in phase I. As of 2017, Spark Therapeutics' Luxturna (RPE65 mutation-induced blindness) and Novartis' Kymriah (Chimeric antigen receptor T cell therapy) are the FDA's first approved gene therapies to enter the market. Since that time, drugs such as Novartis' Zolgensma and Alnylam's Patisiran have also received FDA approval, in addition to other companies' gene therapy drugs. Most of these approaches utilize adeno-associated viruses (AAVs) and lentiviruses for performing gene insertions, in vivo and ex vivo, respectively. ASO / siRNA approaches such as those conducted by Alnylam and Ionis Pharmaceuticals require non-viral delivery systems, and utilize alternative mechanisms for trafficking to liver cells by way of GalNAc transporters.

Disease prevention

Main article: Preventive healthcare

Further information: DNA immunization

See also: Immunocompromisation

Some people are immunocompromised and their bodies are hence much less capable of fending off and defeating diseases (i.e. influenza, ...). In some cases this is due to genetic flaws or even genetic diseases such as SCID. Some gene therapies have already been developed or are being developed to correct these genetic flaws/diseases, hereby making these people less susceptible to catching additional diseases (i.e. influenza, ...).

In November 2018, Lulu and Nana were created. By using clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9, a gene editing technique, they disabled a gene called CCR5 in the embryos, aiming to close the protein doorway that allows HIV to enter a cell and make the subjects immune to the HIV virus.

Gene doping

Main article: Gene doping

Athletes might adopt gene therapy technologies to improve their performance. Gene doping is not known to occur, but multiple gene therapies may have such effects. Kayser et al. argue that gene doping could level the playing field if all athletes receive equal access. Critics claim that any therapeutic intervention for non-therapeutic/enhancement purposes compromises the ethical foundations of medicine and sports.

Other uses

Other hypothetical gene therapies could include changes to physical appearance, metabolism, mental faculties such as memory and intelligence, and well-being (by increasing resistance to depression or relieving chronic pain, for example).

Physical appearance

See also: Morphological freedom

Some congenital disorders (such as those affecting the muscoskeletal system) may affect physical appearance, and in some cases may also cause physical discomfort. Modifying the genes causing these congenital diseases (on those diagnosed to have mutations of the gene known to cause these diseases) may prevent this.

Also changes in the mystatin gene may alter appearance.

Behavior

Further information: Behavioural genetics and Genetics of aggression

Behavior may also be modified by genetic intervention. Some people may be aggressive, selfish, and may not be able to function well in society. There is currently research ongoing on genes that are or may be (in part) responsible for selfishness (e.g. ruthlessness gene), aggression (e.g. warrior gene), altruism (e.g. OXTR, CD38, COMT, DRD4, DRD5, IGF2, GABRB2)

There is some research going on on the hypothetical treatment of psychiatric disorders by means of gene therapy. It is assumed that, with gene-transfer techniques, it is possible (in experimental settings using animal models) to alter CNS gene expression and thereby the intrinsic generation of molecules involved in neural plasticity and neural regeneration, and thereby modifying ultimately behaviour.

In recent years, it was possible to modify ethanol intake in animal models. Specifically, this was done by targeting the expression of the aldehyde dehydrogenase gene (ALDH2), lead to a significantly altered alcohol-drinking behaviour. Reduction of p11, a serotonin receptor binding protein, in the nucleus accumbens led to depression-like behaviour in rodents, while restoration of the p11 gene expression in this anatomical area reversed this behaviour.

Recently, it was also shown that the gene transfer of CBP (CREB (c-AMP response element binding protein) binding protein) improves cognitive deficits in an animal model of Alzheimer's dementia via increasing the expression of BDNF (brain-derived neurotrophic factor). The same authors were also able to show in this study that accumulation of amyloid-β (Aβ) interfered with CREB activity which is physiologically involved in memory formation.

In another study, it was shown that Aβ deposition and plaque formation can be reduced by sustained expression of the neprilysin (an endopeptidase) gene which also led to improvements on the behavioural (i.e. cognitive) level.

Similarly, the intracerebral gene transfer of ECE (endothelin-converting enzyme) via a virus vector stereotactically injected in the right anterior cortex and hippocampus, has also shown to reduce Aβ deposits in a transgenic mouse model of Alzeimer's dementia.

There is also research going on on genoeconomics, a protoscience that is based on the idea that a person's financial behavior could be traced to their DNA and that genes are related to economic behavior. As of 2015, the results have been inconclusive. Some minor correlations have been identified.

Databases about potential modifications

George Church has compiled a list of potential genetic modifications based on scientific studies for possibly advantageous traits such as less need for sleep, cognition-related changes that protect against Alzheimer's disease, disease resistances, higher lean muscle mass and enhanced learning abilities along with some of the associated studies and potential negative effects.

An illustration of viral vector-mediated gene transfer using an adenovirus as the vector.

Human genetic enhancement or human genetic engineering refers to human enhancement by means of a genetic modification. This could be done in order to cure diseases (gene therapy), prevent the possibility of getting a particular disease (similarly to vaccines), to improve athlete performance in sporting events (gene doping), or to change physical appearance, metabolism, and even improve physical capabilities and mental faculties such as memory and intelligence. These genetic enhancements may or may not be done in such a way that the change is heritable (which has raised concerns within the scientific community).

Gene therapy

Further information: Gene therapy

Genetic modification in order to cure genetic diseases is referred to as gene therapy. Many such gene therapies are available, made it through all phases of clinical research and are approved by the FDA. Between 1989 and December 2018, over 2,900 clinical trials were conducted, with more than half of them in phase I. As of 2017, Spark Therapeutics' Luxturna (RPE65 mutation-induced blindness) and Novartis' Kymriah (Chimeric antigen receptor T cell therapy) are the FDA's first approved gene therapies to enter the market. Since that time, drugs such as Novartis' Zolgensma and Alnylam's Patisiran have also received FDA approval, in addition to other companies' gene therapy drugs. Most of these approaches utilize adeno-associated viruses (AAVs) and lentiviruses for performing gene insertions, in vivo and ex vivo, respectively. ASO / siRNA approaches such as those conducted by Alnylam and Ionis Pharmaceuticals require non-viral delivery systems, and utilize alternative mechanisms for trafficking to liver cells by way of GalNAc transporters.

Disease prevention

Main article: Preventive healthcare

Further information: DNA immunization

See also: Immunocompromisation

Some people are immunocompromised and their bodies are hence much less capable of fending off and defeating diseases (i.e. influenza, ...). In some cases this is due to genetic flaws or even genetic diseases such as SCID. Some gene therapies have already been developed or are being developed to correct these genetic flaws/diseases, hereby making these people less susceptible to catching additional diseases (i.e. influenza, ...).

In November 2018, Lulu and Nana were created. By using clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9, a gene editing technique, they disabled a gene called CCR5 in the embryos, aiming to close the protein doorway that allows HIV to enter a cell and make the subjects immune to the HIV virus.

Gene doping

Main article: Gene doping

Athletes might adopt gene therapy technologies to improve their performance. Gene doping is not known to occur, but multiple gene therapies may have such effects. Kayser et al. argue that gene doping could level the playing field if all athletes receive equal access. Critics claim that any therapeutic intervention for non-therapeutic/enhancement purposes compromises the ethical foundations of medicine and sports.

Other uses

Other hypothetical gene therapies could include changes to physical appearance, metabolism, mental faculties such as memory and intelligence, and well-being (by increasing resistance to depression or relieving chronic pain, for example).

Physical appearance

See also: Morphological freedom

Some congenital disorders (such as those affecting the muscoskeletal system) may affect physical appearance, and in some cases may also cause physical discomfort. Modifying the genes causing these congenital diseases (on those diagnosed to have mutations of the gene known to cause these diseases) may prevent this.

Also changes in the mystatin gene may alter appearance.

Behavior

Further information: Behavioural genetics and Genetics of aggression

Behavior may also be modified by genetic intervention. Some people may be aggressive, selfish, and may not be able to function well in society. There is currently research ongoing on genes that are or may be (in part) responsible for selfishness (e.g. ruthlessness gene), aggression (e.g. warrior gene), altruism (e.g. OXTR, CD38, COMT, DRD4, DRD5, IGF2, GABRB2)

There is some research going on on the hypothetical treatment of psychiatric disorders by means of gene therapy. It is assumed that, with gene-transfer techniques, it is possible (in experimental settings using animal models) to alter CNS gene expression and thereby the intrinsic generation of molecules involved in neural plasticity and neural regeneration, and thereby modifying ultimately behaviour.

In recent years, it was possible to modify ethanol intake in animal models. Specifically, this was done by targeting the expression of the aldehyde dehydrogenase gene (ALDH2), lead to a significantly altered alcohol-drinking behaviour. Reduction of p11, a serotonin receptor binding protein, in the nucleus accumbens led to depression-like behaviour in rodents, while restoration of the p11 gene expression in this anatomical area reversed this behaviour.

Recently, it was also shown that the gene transfer of CBP (CREB (c-AMP response element binding protein) binding protein) improves cognitive deficits in an animal model of Alzheimer's dementia via increasing the expression of BDNF (brain-derived neurotrophic factor). The same authors were also able to show in this study that accumulation of amyloid-β (Aβ) interfered with CREB activity which is physiologically involved in memory formation.

In another study, it was shown that Aβ deposition and plaque formation can be reduced by sustained expression of the neprilysin (an endopeptidase) gene which also led to improvements on the behavioural (i.e. cognitive) level.

Similarly, the intracerebral gene transfer of ECE (endothelin-converting enzyme) via a virus vector stereotactically injected in the right anterior cortex and hippocampus, has also shown to reduce Aβ deposits in a transgenic mouse model of Alzeimer's dementia.

There is also research going on on genoeconomics, a protoscience that is based on the idea that a person's financial behavior could be traced to their DNA and that genes are related to economic behavior. As of 2015, the results have been inconclusive. Some minor correlations have been identified.

Databases about potential modifications

George Church has compiled a list of potential genetic modifications based on scientific studies for possibly advantageous traits such as less need for sleep, cognition-related changes that protect against Alzheimer's disease, disease resistances, higher lean muscle mass and enhanced learning abilities along with some of the associated studies and potential negative effects.

Lentivirus

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Lentivirus 

 

Lentivirus
Virus classification
(unranked):	Virus
Realm:	Riboviria
Kingdom:	Pararnavirae
Phylum:	Artverviricota
Class:	Revtraviricetes
Order:	Ortervirales
Family:	Retroviridae
Subfamily:	Orthoretrovirinae
Genus:	Lentivirus
Species
Bovine immunodeficiency virus Caprine arthritis encephalitis virus Equine infectious anemia virus Feline immunodeficiency virus Human immunodeficiency virus 1 Human immunodeficiency virus 2 Jembrana disease virus Puma lentivirus Simian immunodeficiency virus Visna-maedi virus (+5 endogenous found)

Lentivirus is a genus of retroviruses that cause chronic and deadly diseases characterized by long incubation periods, in humans and other mammalian species. The genus includes the human immunodeficiency virus (HIV), which causes AIDS. Lentiviruses are distributed worldwide, and are known to be hosted in apes, cows, goats, horses, cats, and sheep as well as several other mammals.

Lentiviruses can integrate a significant amount of viral complementary DNA into the DNA of the host cell and can efficiently infect nondividing cells, so they are one of the most efficient methods of gene delivery. They can become endogenous, integrating their genome into the host germline genome, so that the virus is henceforth inherited by the host's descendants.

Classification

Five serogroups of lentiviruses are recognized, reflecting the vertebrate hosts with which they are associated (primates, sheep and goats, horses, domestic cats, and cattle). The primate lentiviruses are distinguished by the use of CD4 protein as a receptor and the absence of dUTPase. Some groups have cross-reactive gag antigens (e.g., the ovine, caprine, and feline lentiviruses). Antibodies to gag antigens in lions and other large felines indicate the existence of another yet to be identified virus related to feline lentivirus and the ovine/caprine lentiviruses.

Morphology

Structure of HIV, a lentivirus.

The virions are enveloped viruses 80–100 nm in diameter. They are spherical or pleomorphic, with capsid cores that mature to a cylindrical or conical shape. Projections of envelope make the surface appear rough, or tiny spikes (about 8 nm) may be dispersed evenly over the surface.

Genome organization and replication

As with all retroviruses, lentiviruses have gag, pol and env genes, coding for viral proteins in the order: 5´-gag-pol-env-3´. Unlike other retroviruses, however, lentiviruses have two regulatory genes, tat and rev. They may also have additional accessory genes depending on the virus (e.g., for HIV-1: vif, vpr, vpu, nef) whose products are involved in regulation of synthesis and processing viral RNA and other replicative functions. The Long terminal repeat (LTR) is about 600 nt long, of which the U3 region is 450, the R sequence 100 and the U5 region some 70 nt long.

Retroviruses carry specific proteins within their capsids, which typically associate with the RNA genome. These proteins are typically involved in the early stages of genome replication, and include reverse transcriptase and integrase. Reverse transcriptase is the virally encoded RNA-dependent DNA polymerase. The enzyme uses the viral RNA genome as a template for the synthesis of a complementary DNA copy. Reverse transcriptase also has RNaseH activity for destruction of the RNA-template. Integrase binds both the viral cDNA generated by reverse transcriptase and the host DNA. Integrase processes the LTR before inserting the viral genome into the host DNA. Tat acts as a trans-activator during transcription to enhance initiation and elongation. The Rev responsive element acts post-transcriptionally, regulating mRNA splicing and transport to the cytoplasm.

Proteome

Further information: Structure and genome of HIV § Genome organization

The lentiviral proteome consists of five major structural proteins and 3-4 non-structural proteins (3 in the primate lentiviruses).

Structural proteins listed by size:

1. Gp120 surface envelope protein SU, encoded by the viral gene env. 120000 Da (Daltons).
2. Gp41 transmembrane envelope protein TM, also encoded by the viral gene env. 41000 Da.
3. P24 capsid protein CA, encoded by the viral gene gag. 24000 Da.
4. P17 matrix protein MA, also encoded by gag. 17000 Da.
5. P7/P9 capsid protein NC, also encoded by gag. 7000-11000 Da.

The envelope proteins SU and TM are glycosylated in at least some lentiviruses (HIV, SIV), if not all of them. Glycosylation seems to play a structural role in the concealment and variation of antigenic sites necessary for the host to mount an immune system response.

Enzymes:

1. Reverse transcriptase RT encoded by the pol gene. Protein size 66000 Da.
2. Integrase IN also encoded by the pol gene. Protein size 32000 Da.
3. Protease PR encoded by the pro gene (part of pol gene in some viruses).
4. dUTPase DU encoded by the pro gene (part of pol gene in some viruses), the role of which is still unknown. Protein size 14000 Da.

Gene regulatory proteins:

1. Tat: main trans-activator
2. Rev: important for synthesis of major viral proteins

Accessory proteins:

1. Nef: negative factor
2. Vpr: regulatory protein
3. Vif: APOBEC3 inhibitor
4. Vpu/Vpx: unique to each type of HIV
5. p6: part of gag

Antigenic properties

Serological relationships: Antigen determinants are type-specific and group-specific. Antigen determinants that possess type-specific reactivity are found on the envelope. Antigen determinants that possess type-specific reactivity and are involved in antibody mediated neutralization are found on the glycoproteins. Cross-reactivity has been found among some species of the same serotype, but not between members of different genera. Classification of members of this taxon is infrequently based on their antigenic properties.

Epidemiology

• Symptoms and host range: the virus's hosts are found in the orders Primates (humans, apes and monkeys), Carnivora (cats, dogs and other carnivores), Perissodactyla and Artiodactyla (single and double-toed hooved mammals).
• Transmission: transmitted by means not involving a vector.
• Geographic distribution: worldwide.

Physicochemical and physical properties

• General
  • Buoyant density 1.16–1.18 g cm⁻³ in sucrose
  • Virions sensitive to heat, detergents, and formaldehyde
  • Infectivity not affected by UV irradiation

Classed as having class C morphology

Lentiviral delivery of designed shRNA's and the mechanism of RNA interference in mammalian cells.

• Nucleic acid
  • Virions contain 2% nucleic acid
  • Genome consists of a dimer
  • Virions contain one molecule of (each) linear positive-sense single stranded RNA.
  • Total genome length is of one monomer ranges from 8k-10k nt (depending on the virus).
  • Genome sequence has terminal repeated sequences; long terminal repeats (LTR) (of about 600 nt)
  • The 5' end of the genome has a cap
  • Cap sequence of type 1 m7G5ppp5'GmpNp
  • 3' end of each monomer has a poly (A) tract.
  • 2 copies packed per particle (held together by Watson-Crick baseparing to form a dimer).
• There are 11 proteins
  • Virions contain 60% protein
  • Five (major)structural virion proteins have been found so far
• Lipids: Virions contain 35% lipid.
• Carbohydrates: Other compounds detected in the particles 3% carbohydrates.

Use as gene delivery vectors

Main article: Lentiviral vector in gene therapy

Lentivirus is primarily a research tool used to introduce a gene product into in vitro systems or animal models. Large-scale collaborative efforts are underway to use lentiviruses to block the expression of a specific gene using RNA interference technology in high-throughput formats. Conversely, lentivirus are also used to stably over-express certain genes, thus allowing researchers to examine the effect of increased gene expression in a model system.

Another common application is to use a lentivirus to introduce a new gene into human or animal cells. For example, a model of mouse hemophilia is corrected by expressing wild-type platelet-factor VIII, the gene that is mutated in human hemophilia. Lentiviral infection has advantages over other gene-therapy methods including high-efficiency infection of dividing and non-dividing cells, long-term stable expression of a transgene, and low immunogenicity. Lentiviruses have also been successfully used for transduction of diabetic mice with the gene encoding PDGF (platelet-derived growth factor), a therapy being considered for use in humans. Finally, lentiviruses have been also used to elicit an immune response against tumor antigens. These treatments, like most current gene therapy experiments, show promise but are yet to be established as safe and effective in controlled human studies. Gammaretroviral and lentiviral vectors have so far been used in more than 300 clinical trials, addressing treatment options for various diseases.

Aging-associated diseases

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Aging-associated_diseases 

 

Age-specific SEER incidence rates, 2003–2007

An aging-associated disease (commonly termed age-related disease, ARD) is a disease that is most often seen with increasing frequency with increasing senescence. They are essentially complications of senescence, distinguished from the aging process itself because all adult animals age (with rare exceptions) but not all adult animals experience all age-associated diseases. The term does not refer to age-specific diseases, such as the childhood diseases chicken pox and measles, only diseases of the elderly. They are also not accelerated aging diseases, all of which are genetic disorders.

Examples of aging-associated diseases are atherosclerosis and cardiovascular disease, cancer, arthritis, cataracts, osteoporosis, type 2 diabetes, hypertension and Alzheimer's disease. The incidence of all of these diseases increases exponentially with age.

Of the roughly 150,000 people who die each day across the globe, about two thirds—100,000 per day—die of age-related causes. In industrialized nations, the proportion is higher, reaching 90%.

Patterns of differences

By age 3, about 30% of rats have had cancer, whereas by age 85 about 30% of humans have had cancer. Humans, dogs and rabbits get Alzheimer's disease, but rodents do not. Elderly rodents typically die of cancer or kidney disease, but not of cardiovascular disease. In humans, the relative incidence of cancer increases exponentially with age for most cancers, but levels off or may even decline by age 60–75 (although colon/rectal cancer continues to increase).

People with the so-called segmental progerias are vulnerable to different sets of diseases. Those with Werner's syndrome experience osteoporosis, cataracts, and, cardiovascular disease, but not neurodegeneration or Alzheimer's disease; those with Down syndrome have type 2 diabetes and Alzheimer's disease, but not high blood pressure, osteoporosis or cataracts. In Bloom syndrome, those affected most often die of cancer.

Research

Aging (senescence) increases vulnerability to age-associated diseases, whereas genetics determines vulnerability or resistance between species and individuals within species. Some age-related changes (like graying hair) are said to be unrelated to an increase in mortality. But some biogerontologists believe that the same underlying changes that cause graying hair also increase mortality in other organ systems and that understanding the incidence of age-associated disease will advance knowledge of the biology of senescence just as knowledge of childhood diseases advanced knowledge of human development.

Strategies for engineered negligible senescence (SENS) is an emerging research strategy that aims to repair "root causes" for age-related illness and degeneration, as well as develop medical procedures to periodically repair all such damage in the human body, thereby maintaining a youth-like state indefinitely. The SENS programme has identified seven types of aging-related damage, and feasible solutions have been outlined for each. Some critics argue that the SENS agenda is optimistic at best, and that the aging process is too complex and little-understood for SENS to be scientific or implementable in the foreseeable future. It has been proposed that age-related diseases are mediated by vicious cycles.

On the basis of extensive research, DNA damage has emerged a major culprit in cancer and numerous other diseases related to ageing. DNA damage can initiate the development of cancer or other aging related diseases depending on several factors. These include the type, amount, and location of the DNA damage in the body, the type of cell experiencing the damage and its stage in the cell cycle, and the specific DNA repair processes available to react to the damage.

Types

Macular degeneration

Age-related macular degeneration (AMD) is a disease that affects the eyes and can lead to vision loss through break down of the central part of the retina called the macula. Degeneration can occur in one eye or both and can be classified as either wet (neovascular) or dry (atrophic). Wet AMD commonly is caused by blood vessels near the retina that lead to swelling of the macula. The cause of dry AMD is less clear, but it is thought to be partly caused by breakdown of light-sensitive cells and tissue surrounding the macula. A major risk factor for AMD is age over the age of 60.

Alzheimer's

Alzheimer's disease is classified as a "protein misfolding" disease. Aging causes mutations in protein folding, and as a result causes deposits of abnormal modified proteins accumulate in specific areas of the brain. In Alzheimer's,deposits of Beta-amyloid and hyperphosphorylated tau protein form extracellular plaques and extracellular tangles. These deposits are shown to be neurotoxic and cause cognitive impairment due to their initiation of destructive biochemical pathways.

Atherosclerosis

Atherosclerosis is categorized as an aging disease and is brought about by vascular remodeling, the accumulation of plaque, and the loss of arterial elasticity. Over time, these processes can stiffen the vasculature. For these reasons, older age is listed as a major risk factor for atherosclerosis. Specifically, the risk of atherosclerosis increases for men above 45 years of age and women above 55 years of age.

Benign prostatic hyperplasia

Benign prostatic hyperplasia (BPH) is a noncancerous enlargement of the prostate gland due to increased growth. An enlarged prostate can result in incomplete or complete blockage of the bladder and interferes with a man's ability to urinate properly. Symptoms include overactive bladder, decreased stream of urine, hesitancy urinating, and incomplete emptying of the bladder. By age 40, 10% of men will have signs of BPH and by age 60, this percentage increases by 5 fold. Men over the age of 80 have over a 90% chance of developing BPH and almost 80% of men will develop BPH in their lifetime.

Cancer

Although it is possible for cancer to strike at any age, most patients with invasive cancer are over 65, and the most significant risk factor for developing cancer is age. According to cancer researcher Robert A. Weinberg, "If we lived long enough, sooner or later we all would get cancer." Some of the association between aging and cancer is attributed to immunosenescence, errors accumulated in DNA over a lifetime and age-related changes in the endocrine system. Aging's effect on cancer is complicated by factors such as DNA damage and inflammation promoting it and factors such as vascular aging and endocrine changes inhibiting it.

Parkinson's

Parkinson's disease, or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The disease has many complications, including Dementia, depression, anxiety. Parkinson's disease typically occurs in people over the age of 60, of whom about one percent are affected. The prevalence of Parkinson's disease dementia also increases with age, and to a lesser degree, duration of the disease. Exercise in middle age may reduce the risk of PD later in life.

Stroke

Stroke was the second most frequent cause of death worldwide in 2011, accounting for 6.2 million deaths (~11% of the total). Stroke could occur at any age, including in childhood, the risk of stroke increases exponentially from 30 years of age, and the cause varies by age. Advanced age is one of the most significant stroke risk factors. 95% of strokes occur in people age 45 and older, and two-thirds of strokes occur in those over the age of 65. A person's risk of dying if he or she does have a stroke also increases with age.

Endocrine diseases

Studies in animal models show that clearance of senescent cells improves multiple age related endocrine disorders.

Osteoporosis

Bone density declines with age. By the age of 85 years, ~70% of women and 30% of men have a osteoporosis defined as a bone density less than or equal to 2.5 standard deviations lower than young adults.

Metabolic syndrome

The metabolic syndrome is the co-occurrence of metabolic risk factors for type 2 diabetes and cardiovascular disease (abdominal obesity, hyperglycemia, dyslipidemia, and hypertension). The prevalence of the metabolic syndrome increases with age reaching close to 50% of people over 60 years old in the USA.

Geriatrics

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Geriatrics 

An elderly woman in a residential care home receiving a birthday cake
Significant diseases	Dementia, arthritis, osteoporosis, osteoarthritis, rheumatoid arthritis, Parkinson's disease, atherosclerosis, heart disease, high blood pressure,
Specialist	Geriatrician

Geriatrician

Occupation
Names	Physician
Occupation type	Specialty
Activity sectors	Medicine
Description
Education required	Doctor of Medicine (M.D.) Doctor of Osteopathic medicine (D.O.) Bachelor of Medicine, Bachelor of Surgery (M.B.B.S.) Bachelor of Medicine, Bachelor of Surgery (MBChB)
Fields of employment	Hospitals, Clinics

Geriatrics, or geriatric medicine, is a medical specialty focused on providing care for the unique health needs of older adults. The term geriatrics originates from the Greek γέρων geron meaning "old man", and ιατρός iatros meaning "healer". It aims to promote health by preventing, diagnosing and treating disease in older adults. There is no defined age at which patients may be under the care of a geriatrician, or geriatric physician, a physician who specializes in the care of elderly people. Rather, this decision is guided by individual patient need and the caregiving structures available to them. This care may benefit those who are managing multiple chronic conditions or experiencing significant age-related complications that threaten quality of daily life. Geriatric care may be indicated if caregiving responsibilities become increasingly stressful or medically complex for family and caregivers to manage independently.

There is a distinction between geriatrics and gerontology. Gerontology is the multidisciplinary study of the aging process, defined as the decline in organ function over time in the absence of injury, illness, environmental risks or behavioral risk factors. However, geriatrics is sometimes called medical gerontology.

Scope

Elderly man at a nursing home in Norway

Differences between adult and geriatric medicine

Geriatric providers receive specialized training in caring for elderly patients and promoting healthy aging. The care provided is one largely based on shared-decision making and is driven by patient goals and preferences, which can vary from preserving function, improving quality of life, or prolonging years of life. A guiding mnemonic commonly used by geriatricians in the United States and Canada is the 5 M's of Geriatrics which describes mind, mobility, multicomplexity, medications and matters most to elicit patient values.

It is common for elderly adults to be managing multiple medical conditions, or, multi-morbidity. Age-associated changes in physiology drive a compounded increase in susceptibility to illness, disease-associated morbidity, and death. Furthermore, common diseases may present atypically in elderly patients, adding further diagnostic and therapeutical complexity in patient care.

Geriatrics is highly interdisciplinary consisting of specialty providers from the fields of medicine, nursing, pharmacy, social work, physical and occupational therapy. Elderly patients can receive care related to medication management, pain management, psychiatric and memory care, rehabilitation, long-term nursing care, nutrition and different forms of therapy including physical, occupational and speech. Non-medical considerations include social services, transitional care, advanced directives, power of attorney and other legal considerations.

Increased complexity

The decline in physiological reserve in organs makes the elderly develop some kinds of diseases and have more complications from mild problems (such as dehydration from a mild gastroenteritis). Multiple problems may compound: A mild fever in elderly persons may cause confusion, which may lead to a fall and to a fracture of the neck of the femur ("broken hip").

The presentation of disease in elderly persons may be vague and non-specific, or it may include delirium or falls. (Pneumonia, for example, may present with low-grade fever and confusion, rather than the high fever and cough seen in younger people.) Some elderly people may find it hard to describe their symptoms in words, especially if the disease is causing confusion, or if they have cognitive impairment. Delirium in the elderly may be caused by a minor problem such as constipation or by something as serious and life-threatening as a heart attack. Many of these problems are treatable, if the root cause can be discovered.

Geriatric pharmacology

Elderly people require specific attention to medications. Elderly people particularly are subjected to polypharmacy (taking multiple medications) given their accumulation of multiple chronic diseases. Many of these individuals have also self-prescribed many herbal medications and over-the-counter drugs. This polypharmacy, in combination with geriatric status, may increase the risk of drug interactions or adverse drug reactions. Pharmacokinetic and pharmacodynamic changes arise with older age, impairing their ability to metabolize and respond to drugs. Each of the four pharmacokinetic mechanisms (absorption, distribution, metabolism, excretion) are disrupted by age-related physiologic changes. For example, overall decreased hepatic function can interfere with clearance or metabolism of drugs and reductions in kidney function can affect renal elimination. Pharmacodynamic changes lead altered sensitivity to drugs in geriatric patients, such as increased pain relief with morphine use. Therefore, geriatric individuals require specialized pharmacological care that is informed by these age-related changes.

Geriatric syndromes

Geriatric syndromes is a term used to describe a group of clinical conditions that are highly prevalent in elderly people. These syndromes are not caused by specific pathology or disease, rather, are a manifestation of multifactorial conditions affecting several organ systems. Common conditions include frailty, functional decline, falls, loss in continence and malnutrition, amongst others.

Frailty

Frailty is marked by a decline in physiological reserve, increased vulnerability to physiological and emotional stressors, and loss of function. This may present as progressive and unintentional weight loss, fatigue, muscular weakness and decreased mobility. It is associated with increased injuries, hospitalization and adverse clinical outcomes.

Functional decline

Functional disability can arise from a decline in physical function and/or cognitive function. It is associated with an acquired difficulty in performing basic everyday tasks resulting in an increased dependence of other individuals and/or medical devices. These tasks are sub-divided into basic activities of daily living (ADL) and instrumental activities of daily living (IADL) and are commonly used as an indicator of a person's functional status.

Activities of daily living (ADL) are fundamental skills needed to care for oneself, including feeding, personal hygiene, toileting, transferring and ambulating. Instrumental activities of daily living (IADL) describe more complex skills needed to allow oneself to live independently in a community, including cooking, housekeeping, managing one's finances and medications. Routine monitoring of ADL and IADL is an important functional assessment used by clinicians to determine the extent of support and care to provide to elderly adults and their caregivers. It serves as a qualitative measurement of function over time and predicts the need for alternative living arrangements or models of care, including senior housing apartments, skilled nursing facilities, palliative, hospice or home-based care.

Falls

Falls are the leading cause of emergency department admissions and hospitalizations in adults age 65 and older, many of which result in significant injury and permanent disability. As certain risk factors can be modifiable for the purpose of reducing falls, this highlights an opportunity for intervention and risk reduction. Modifiable factors include:

• Improving balance and muscle strength.
• Removing environmental hazards.
• Encouraging use of assistive devices.
• Treating chronic conditions.
• Adjusting medication.

Urinary incontinence

Urinary incontinence or overactive bladder symptoms is defined as unintentionally urinating oneself. These symptoms can be caused by medications that increase urine output and frequency (e.g. anti-hypertensives and diuretics), urinary tract infections, pelvic organ prolapse, pelvic floor dysfunction, and diseases that damage the nerves that regulate bladder emptying. Other musculoskeletal conditions affecting mobility should be considered, as these can make accessing bathrooms difficult.

Malnutrition

Malnutrition and poor nutritional status is an area of concern, affecting 12% to 50% of hospitalized elderly patients and 23% to 50% of institutionalized elderly patients living in long-term care facilities such as assisted living communities and skilled nursing facilities. As malnutrition can occur due to a combination of physiologic, pathologic, psychologic and socioeconomic factors, it can be difficult to identify effective interventions. Physiologic factors include reduced smell and taste, and a decreased metabolic rate affecting nutritional food intake. Unintentional weight loss can result from pathologic factors, including a wide range of chronic diseases that affect cognitive function, directly impact digestion (e.g. poor dentition, gastrointestinal cancers, gastroesophageal reflux disease) or may be managed with dietary restrictions (e.g. congestive heart failure, diabetes mellitus, hypertension). Psychologic factors include conditions including depression, anorexia, and grief.

Practical concerns

Functional abilities, independence and quality of life issues are of great concern to geriatricians and their patients. Elderly people generally want to live independently as long as possible, which requires them to be able to engage in self-care and other activities of daily living. A geriatrician may be able to provide information about elder care options, and refers people to home care services, skilled nursing facilities, assisted living facilities, and hospice as appropriate.

Frail elderly people may choose to decline some kinds of medical care, because the risk-benefit ratio is different. For example, frail elderly women routinely stop screening mammograms, because breast cancer is typically a slowly growing disease that would cause them no pain, impairment, or loss of life before they would die of other causes. Frail people are also at significant risk of post-surgical complications and the need for extended care, and an accurate prediction—based on validated measures, rather than how old the patient's face looks—can help older patients make fully informed choices about their options. Assessment of older patients before elective surgeries can accurately predict the patients' recovery trajectories. One frailty scale uses five items: unintentional weight loss, muscle weakness, exhaustion, low physical activity, and slowed walking speed. A healthy person scores 0; a very frail person scores 5. Compared to non-frail elderly people, people with intermediate frailty scores (2 or 3) are twice as likely to have post-surgical complications, spend 50% more time in the hospital, and are three times as likely to be discharged to a skilled nursing facility instead of to their own homes. Frail elderly patients (score of 4 or 5) who were living at home before the surgery have even worse outcomes, with the risk of being discharged to a nursing home rising to twenty times the rate for non-frail elderly people.

Subspecialties and related services

Some diseases commonly seen in elderly are rare in adults, e.g., dementia, delirium, falls. As societies aged, many specialized geriatric- and geriatrics-related services emerged including:

Medical

• Geriatric cardiology or cardiogeriatrics.
• Geriatric dentistry.
• Geriatric dermatology.
• Geriatric diagnostic imaging.
• Geriatric emergency medicine.
• Geriatric nephrology.
• Geriatric neurology.
• Geriatric oncology.
• Geriatric physical examination of interest especially to physicians & physician assistants.
• Geriatric psychiatry or psychogeriatrics (focus on dementia, delirium, depression and other psychiatric disorders).
• Geriatric public health or preventive geriatrics
• Geriatric rehabilitation.
• Geriatric rheumatology (focus on joints and soft tissue disorders in elderly).
• Geriatric sexology (focus on sexuality in aged people).
• Geriatric subspeciality medical clinics (such as geriatric anticoagulation clinic, geriatric assessment clinic, falls and balance clinic, continence clinic, palliative care clinic, elderly pain clinic, cognition and memory disorders clinic).

Surgical

• Geriatric orthopaedics or orthogeriatrics (close cooperation with orthopedic surgery and a focus on osteoporosis and rehabilitation).
• Geriatric cardiothoracic surgery.
• Geriatric urology.
• Geriatric otolaryngology.
• Geriatric general surgery.
• Geriatric trauma.
• Geriatric gynecology.
• Geriatric ophthalmology.

Other geriatrics subspecialties

• Geriatric anesthesia (focuses on anesthesia & perioperative care of elderly).
• Geriatric intensive-care unit: (a special type of intensive care unit dedicated to critically ill elderly).
• Geriatric nursing (focuses on nursing of elderly patients and the aged).
• Geriatric nutrition.
• Geriatric occupational therapy.
• Geriatric pain management.
• Geriatric pharmacy.
• Geriatric optometry.
• Geriatric physical therapy.
• Geriatric podiatry.
• Geriatric psychology.
• Geriatric speech-language pathology (focuses on neurological disorders such as dysphagia, stroke, aphasia, and traumatic brain injury).
• Geriatric mental health counselor/specialist (focuses on treatment more so than assessment).
• Geriatric audiology.

History

One of the eight branches of the traditional Indian system of medicine, Ayurveda, is jara or rasayana, similar to geriatrics. Charaka described the fatigue and physical exhaustion caused by premature aging as the result of a poor diet. The Charaka Samhita recommends that elderly patients avoid excessive physical or mental strain and consume a light but nutritious diet.

A number of physicians in the Byzantine Empire studied geriatrics, with doctors like Aëtius of Amida evidently specializing in the field. Alexander of Tralles viewed the process of aging as a natural and inevitable form of marasmus, caused by the loss of moisture in body tissue. The works of Aëtius describe the mental and physical symptoms of aging. Theophilus Protospatharius and Joannes Actuarius also discussed the topic in their medical works. Byzantine physicians typically drew on the works of Oribasius and recommended that elderly patients consume a diet rich in foods that provide "heat and moisture". They also recommended frequent bathing, massaging, rest, and low-intensity exercise regimens.

In The Canon of Medicine, written by Avicenna in 1025, the author was concerned with how "old folk need plenty of sleep" and how their bodies should be anointed with oil, and recommended exercises such as walking or horse-riding. Thesis III of the Canon discussed the diet suitable for old people, and dedicated several sections to elderly patients who become constipated.

The Arab physician Algizar (c. 898–980) wrote a book on the medicine and health of the elderly. He also wrote a book on sleep disorders and another one on forgetfulness and how to strengthen memory, and a treatise on causes of mortality. Another Arab physician in the 9th century, Ishaq ibn Hunayn (died 910), the son of Nestorian Christian scholar Hunayn Ibn Ishaq, wrote a Treatise on Drugs for Forgetfulness.

George Day published the Diseases of Advanced Life in 1849, one of the first publications on the subject of geriatric medicine. The first modern geriatric hospital was founded in Belgrade, Serbia, in 1881 by doctor Laza Lazarević.

The term geriatrics was proposed in 1908 by Ilya Ilyich Mechnikov, Laurate of the Nobel Prize for Medicine and later by 1909 by Dr. Ignatz Leo Nascher, former Chief of Clinic in the Mount Sinai Hospital Outpatient Department (New York City) and a "father" of geriatrics in the United States.

Modern geriatrics in the United Kingdom began with the "mother" of geriatrics, Dr. Marjory Warren. Warren emphasized that rehabilitation was essential to the care of older people. Using her experiences as a physician in a London Workhouse infirmary, she believed that merely keeping older people fed until they died was not enough; they needed diagnosis, treatment, care, and support. She found that patients, some of whom had previously been bedridden, were able to gain some degree of independence with the correct assessment and treatment.

The practice of geriatrics in the UK is also one with a rich multidisciplinary history. It values all the professions, not just medicine, for their contributions in optimizing the well-being and independence of older people.

Another innovator of British geriatrics is Bernard Isaacs, who described the "giants" of geriatrics mentioned above: immobility and instability, incontinence, and impaired intellect. Isaacs asserted that, if examined closely enough, all common problems with older people relate to one or more of these giants.

The care of older people in the UK has been advanced by the implementation of the National Service Frameworks for Older People, which outlines key areas for attention.

Geriatrician training

United States

In the United States, geriatricians are primary-care physicians (D.O. or M.D.) who are board-certified in either family medicine or internal medicine and who have also acquired the additional training necessary to obtain the Certificate of Added Qualifications (CAQ) in geriatric medicine. Geriatricians have developed an expanded expertise in the aging process, the impact of aging on illness patterns, drug therapy in seniors, health maintenance, and rehabilitation. They serve in a variety of roles including hospital care, long-term care, home care, and terminal care. They are frequently involved in ethics consultations to represent the unique health and diseases patterns seen in seniors. The model of care practiced by geriatricians is heavily focused on working closely with other disciplines such as nurses, pharmacists, therapists, and social workers.

United Kingdom

In the United Kingdom, most geriatricians are hospital physicians, whereas others focus on community geriatrics in particular. Although originally a distinct clinical specialty, it has been integrated as a specialization of general medicine since the late 1970s. Most geriatricians are, therefore, accredited for both. Unlike in the United States, geriatric medicine is a major specialty in the United Kingdom and are the single most numerous internal medicine specialists.

Canada

In Canada, there are two pathways that can be followed in order to work as a physician in a geriatric setting.

1. Doctors of Medicine (M.D.) can complete a three-year core internal medicine residency program, followed by two years of specialized geriatrics residency training. This pathway leads to certification, and possibly fellowship after several years of supplementary academic training, by the Royal College of Physicians and Surgeons of Canada.
2. Doctors of Medicine (M.D.) can opt for a two-year residency program in family medicine and complete a one-year enhanced skills program in care of the elderly. This post-doctoral pathway is accredited by the College of Family Physicians of Canada.

Many universities across Canada also offer gerontology training programs for the general public, such that nurses and other health care professionals can pursue further education in the discipline in order to better understand the process of aging and their role in the presence of older patients and residents.

India

In India, Geriatrics is a relatively new speciality offering. A three-year post graduate residency (M.D) training can be joined for after completing the 5.5-year undergraduate training of MBBS (Bachelor of Medicine and Bachelor of Surgery). Unfortunately, only eight major institutes provide M.D in Geriatric Medicine and subsequent training. Training in some institutes are exclusive in the Department of Geriatric Medicine, with rotations in Internal medicine, medical subspecialties etc. but in certain institutions, are limited to 2-year training in Internal medicine and subspecialities followed by one year of exclusive training in Geriatric Medicine.

Minimum geriatric competencies

In July 2007, the Association of American Medical Colleges (AAMC) and the John A. Hartford Foundation hosted a National Consensus Conference on Competencies in Geriatric Education where a consensus was reached on minimum competencies (learning outcomes) that graduating medical students needed to assure competent care by new interns to older patients. Twenty-six (26) Minimum Geriatric Competencies in eight content domains were endorsed by the American Geriatrics Society (AGS), the American Medical Association (AMA), and the Association of Directors of Geriatric Academic Programs (ADGAP). The domains are: cognitive and behavioral disorders; medication management; self-care capacity; falls, balance, gait disorders; atypical presentation of disease; palliative care; hospital care for elders, and health care planning and promotion. Each content domain specifies three or more observable, measurable competencies.

Research

Changes in physiology with aging may alter the absorption, the effectiveness and the side effect profile of many drugs. These changes may occur in oral protective reflexes (dryness of the mouth caused by diminished salivary glands), in the gastrointestinal system (such as with delayed emptying of solids and liquids possibly restricting speed of absorption), and in the distribution of drugs with changes in body fat and muscle and drug elimination.

Psychological considerations include the fact that elderly persons (in particular, those experiencing substantial memory loss or other types of cognitive impairment) are unlikely to be able to adequately monitor and adhere to their own scheduled pharmacological administration. One study (Hutchinson et al., 2006) found that 25% of participants studied admitted to skipping doses or cutting them in half. Self-reported noncompliance with adherence to a medication schedule was reported by a striking one-third of the participants. Further development of methods that might possibly help monitor and regulate dosage administration and scheduling is an area that deserves attention.

Another important area is the potential for improper administration and use of potentially inappropriate medications, and the possibility of errors that could result in dangerous drug interactions. Polypharmacy is often a predictive factor (Cannon et al., 2006). Research done on home/community health care found that "nearly 1 of 3 medical regimens contain a potential medication error" (Choi et al., 2006).

Ethical and medico-legal issues

Elderly persons sometimes cannot make decisions for themselves. They may have previously prepared a power of attorney and advance directives to provide guidance if they are unable to understand what is happening to them, whether this is due to long-term dementia or to a short-term, correctable problem, such as delirium from a fever.

Geriatricians must respect the patients' privacy while seeing that they receive appropriate and necessary services. More than most specialties, they must consider whether the patient has the legal responsibility and competence to understand the facts and make decisions. They must support informed consent and resist the temptation to manipulate the patient by withholding information, such as the dismal prognosis for a condition or the likelihood of recovering from surgery at home.

Elder abuse is the physical, financial, emotional, sexual, or other type of abuse of an older dependent. Adequate training, services, and support can reduce the likelihood of elder abuse, and proper attention can often identify it. For elderly people who are unable to care for themselves, geriatricians may recommend legal guardianship or conservatorship to care for the person or the estate.

Elder abuse occurs increasingly when caregivers of elderly relatives have a mental illness. These instances of abuse can be prevented by engaging these individuals with mental illness in mental health treatment. Additionally, interventions aimed at decreasing elder reliance on relatives may help decrease conflict and abuse. Family education and support programs conducted by mental health professionals may also be beneficial for elderly patients to learn how to set limits with relatives with psychiatric disorders without causing conflict that leads to abuse.