Number of deaths for leading causes of death
Heart disease: 599,413
Cancer: 567,628
Chronic lower respiratory diseases: 137,353
Stroke (cerebrovascular diseases): 128,842
Accidents (unintentional injuries): 118,021
Alzheimer’s disease: 79,003
Diabetes: 68,705
Influenza and Pneumonia: 53,692
Nephritis, nephrotic syndrome, and nephrosis: 48,935
Intentional self-harm (suicide): 36,909 _CDC US Leading Causes of Death

As shown above, stroke — cerebrovascular accident (CVA) — is the 4th ranking cause of death in the US. Besides mortality, there is also significant morbidity and disability associated with stroke worldwide.

Recent research at Toronto Western Hospital provides reason to hope for better drug treatments for stroke in the near future. The researchers tested a new type of drug — a PSD-95 inhibitor — in primates, in an acute stroke setting. Some of their results are pictured below.

A phase 2 clinical trial in humans was also recently completed in Ontario.

In a series of experiments, Michael Tymianski and colleagues at Toronto Western Hospital in Ontario, Canada, replicated the effects of stroke in macaques before intravenously administering a PSD-95 inhibitor, or a placebo. PSD-95 inhibitors interfere with the process that triggers cell death when the brain is deprived of oxygen.

To test its effectiveness the team used MRI to measure the volume of damaged brain for 30 days following the treatment, and conducted behavioural tests at various intervals within this time.

Monkeys treated with the PSD-95 inhibitor one hour after stroke had 55 per cent less damaged tissue in the brain after 24 hours and 70 per cent less after 30 days, compared with those that took a placebo. These animals also did better in behavioural tests. Importantly, the drug was also effective three hours after stroke.

…An early stage clinical trial in humans, run by firm NoNO in Ontario has also seen positive results. _NewScientist

Nature study abstract

PSD-95 Overview

PSD-95 complex as drug target for antidepressant development

The Role of PSD-95 and Cypin in Morphological Changes in Dendrites Following Sublethal NMDA Exposure Interesting abstract providing information on underlying factors involved.

This is a line of treatment which has been obvious for decades, but which has lacked the proper basic science backing up until now. Although PSD-95 inhibitors will not prevent all brain damage from occurring in stroke, nor will they restore damaged brain to normal function afterward, they do seem to limit the amount of damage that occurs, for each stroke.

It is a type of stop-gap measure, meant to prolong relative normal function as long as possible. More optimal developments for the future will involve better preventive measures and ways to rejuvenate damaged brain after the insult occurs. Full spectrum medical care will eventually involve all avenues of treatment, prevention, and restoration.

Al Fin Longevity

The ongoing study of current cognitive enhancers such as those in the table above, have given us scattered hints as to what future therapies might offer. Here is a short list of possible future targets for cognitive therapies:

Among targets under investigation, cholinergic receptors have received much attention with several nicotinic agonists (α7 and α4β2) actively in clinical trials for the treatment of AD, CIAS and attention deficit hyperactivity disorder (ADHD). Both glutamatergic and serotonergic (5-HT) agonists and antagonists have profound effects on neurotransmission and improve cognitive function in preclinical experiments with animals; some of these compounds are now in proof-of-concept studies in humans. Several histamine H3 receptor antagonists are in clinical development not only for cognitive enhancement, but also for the treatment of narcolepsy and cognitive deficits due to sleep deprivation because of their expression in brain sleep centers. Compounds that dampen inhibitory tone (e.g., GABAA α5 inverse agonists) or elevate excitatory tone (e.g., glycine transporter inhibitors) offer novel approaches for treating diseases such as schizophrenia, AD and Down syndrome. In addition to cell surface receptors, intracellular drug targets such as the phosphodiesterases (PDEs) are known to impact signaling pathways that affect long-term memory formation and working memory. Overall, there is a genuine need to treat cognitive deficits associated with many neuropsychiatric conditions as well as an increasingly aging population. _Source

It is important for us, at the outset, to take as realistic a viewpoint toward the possibility of meaningful cognitive enhancement as possible. The Likelihood of Cognitive Enhancement (Lynch et al 2011 PDF) is a useful introduction to many of the practical issues that need to be faced from the very beginning of this enterprise. Cognitive Enhacement: Promises and Perils (Hyman 2011 PDF) is a less technical introduction to the topic, perhaps more accessible to most laymen.

Cognitive Enhancement as a Pharmacotherapy Target for Stimulant Addiction (Sofuoglu 2010) looks at the use of cognitive enhancers as possible treatments for cocaine and methamphetamine addictions. Long term and heavy use of these drugs leads to cognitive deficits which make it even more difficult for a person to stop using these drugs and lead a “normal” life. The restoration of cognitive function is likely to provide a certain amount of “mental fortification” to allow at least some addicts to turn away from the dead end lifestyle. Similarly, restoration of cognitive function in persons suffering from age-related neurodegeneration is more likely to allow the person to participate in normal social interaction, and to undertake some level of responsibility, and perhaps productive activity.

Emerging Pharmacotherapies for Neurodevelopmental Disorders (Wetmore et Garner 2010) looks at the use of cognitive enhancers for persons who suffer from neurodevelopmental disorders such as Down’s Syndrome, Fragile X, autism, etc. Given the overlap of mechanisms between some of the cognitive deficits in developmental disorders and ageing-related cognitive deficits, some of the coming developments in this area of pharmacotherapy should also prove quite helpful for treating age-related dementias.

As more is learned about the time-course of dysfunction in NDDs [neurodevelopmental disorders], targeting of therapies to the existing brain state may be improved. Moreover, individuals with NDDs have multiple cognitive and behavioral disabilities, and a particular drug therapy may improve only a subset of cognitive functions. Thus, a combination of complementary drugs may offer the most benefit by addressing deficits in attention, arousal, information processing, or depression.
…
The NDDs discussed here are phenotypically diverse yet linked by common mechanisms of dysfunction, including abnormal gene dosage, imbalance among neurotransmitter systems, and local protein translation (Fig. 2). A particular NDD can be caused by mutations in multiple genes, underscoring the convergence of dysfunction in key biochemical pathways. _Source

Finally, I would like to append to this entry some material from an earlier Al Fin article, which provides a few hints of future drug targets, as well as links to related material:

AMPAkines
CREB
PDE Inhibitors(4,10)
Nicotinic Alpha-7 agonists
mGluR antagonists
5HT6 antagonists

Frontrunners in the pharmaceutical race for smarter, better memory drugs include Memory Pharmaceuticals, Cortex Pharmaceuticals, Saegis Pharmaceuticals, Helicon, Lilly, Pfizer, Wyeth, Merck, Sention and many others. The precedent of approving drugs for erectile dysfunction (ED)–a lifestyle drug–suggests that smart drugs will eventually be approved for drooping memories as well.

Further Reading:

Molecules for Memory

Nootropics

Smart Drugs: What Are the Prospects?

Shaping the Brain with Smart Drugs (Gazzaniga)

CREB and Memory (basic neuroscience)

CREB, Synapses, and Memory Disorders

Hat tip Advanced Nano and Kurzweilai.net

Al Fin Longevity

(previous session)

Matt Hirschey (Verdin Lab, UCSF-Gladstone): Lack of SIRT3 results in the metabolic syndrome. SIRT3 is a mitochondrial sirtuin (NAD+-dependent deacetylase) that is upregulated in liver upon fasting; knockout mice (SIRT3KO) are grossly normal but have trouble with lipid metabolism (specifically, beta-oxidation). Hershey identified several mitochondrial proteins involved in lipid oxidation that are deacetylated in response to fasting, in wildtype but not SIRT3KO. The knockouts are prone to developing obesity and metabolic syndrome with age.

Kate Brown (Chen lab, UC-Berkeley): Calorie restriction reduces oxidative stress by inducing SIRT3. Beginning with an invocation of the free radical theory of aging, and the observation that calorie restriction (CR) reduces oxidative stress, Brown asked whether the mitochondrial sirtuin SIRT3 could be involved in resistance to reactive oxygen species. She showed that CR induces SIRT3 expression, and that the SIRT3 protein deacetylates the mitochondrial antioxidant enzyme SOD2. Furthermore, consistent with Subhash Katewa’s talk in the first session, she demonstrated that CR reduces oxidative stress by switching from glucose to fatty acid oxidation, and that this switch requires SIRT3 activity.

(We’ve discussed SIRT3 before, most recently regarding its role as a tumor suppressor and also with respect to its relationship with exercise).

Ruth Tennen (Chua lab, Stanford): Insight into SIRT6 function at telomeres and beyond. Another member of the sirtuin family, SIRT6, is not localized to mitochondria but rather to telomeres, where it maintains telomeric chromatin in a healthy state and regulates the activity of the senescence-associated transcription factor NF-κB – for more background, see this previous post.) Tennen has shown that SIRT6 is involved in regulating the telomere position effect (TPE) – the silencing of gene expression caused by proximity to a telomere. The TPE has been implicated in age-related changes in gene expression: as telomeres shorten over time, telomere-proximal genes are aberrantly expressed — meanwhile, silencing factors are liberated to wander throughout the genome, repressing genes that should be turned on; similar logic has been applied to the relationship between DNA damage and transcriptional dysregulation.

Jue Lin (Blackburn Lab, UCSF): Telomere length maintenance and aging-related diseases. This talk described work that builds on significant progress, from this lab and others, demonstrating relationships between telomere length and stress, psychological outlook, and lifespan. Lin reviewed evidence that perceived stress is correlated with telomere length in white blood cells (consistent with previous results showing a relationship with intrusive thoughts). New-to-me data included a demonstration that people who increased omega-3 levels or made favorable lifestyle changes exhibited a slower rate of telomere shortening.

(next session)

Ouroboros

Animal studies support a cancer-promoting role for fat, and in humans, epidemiological data strongly suggest that dietary fat intake may be associated with incidence and mortality of cancers of the breast, colon, rectum, and prostate. There are also data implicating fat in cancers of the ovaries, uterus, pancreas, and lung, but the evidence is not as strong. There is still a debate as to whether it is total dietary fat, specific fats, or total calories that are involved in carcinogenesis. In any event, cancers of breast, colon, and prostate are highest in North America and western Europe and lowest in Asia, and are directly related to the intake of total fat in the diet even when adjusted for total calories. (more…)

Cancer Genetic Markers Of Susceptibility is based after populations in the NCI Cohort Range in addition to collaborative case-control epidemiologic reports by using biospecimens. Through scanning that DNA collected from men and women participating in these kinds of reports, may get determined handed down genetic versions associated with cancer tumor possibility that may bring about fresh preventive, analysis, in addition to restorative interventions. (more…)

Research indicates that anxiety symptoms are more prevalent in elderly people than in any other age group, occurring at about twice the rate of younger adults. The types of anxiety disorders most common among the older population include generalized anxiety, mixed anxious-depressive syndrome symptoms, and phobias (often characterized by exaggerations of rational concerns). More rare are late-life onset of obsessive compulsive disorders (OCD) and panic disorders. (more…)

Depression is the most common mental health problem in the elderly. While the incidence in community-dwelling older adults is no higher than in the general population, the risk increases significantly with medical illness or institutionalization. Depression is probably the best researched of the psychiatric disorders in the elderly, with epidemiological evidence indicating that older adults have the highest suicide rate of any age group (one-fourth of all suicides are carried out by persons age 60 or older by taking sleeping pills suicide). (more…)

Cognitive-Behavioral Interventions Research documenting the efficacy of Cognitive-Behavioral Interventions in treating the psychological problems of older adults is encouraging. Cognitive-Behavioral Interventions has been shown to reduce symptoms of depression, anxiety, and somatic complaints (e.g., chronic pain elderly, insomnia) in multiple controlled studies. However, research also has indicated that there may be multiple variables to consider in determining whether Cognitive-Behavioral Interventions is the best approach to use with a specific patient and a specific problem. For example, differential effectiveness of Cognitive-Behavioral Interventions compared to other forms of psychotherapy is less certain. (more…)

Dyskeratosis congenita is of special interest to gerontologists because it is caused by a mutation in the gene coding for the RNA component of telomerase, an enzyme that is essential for maintenance of the ends of chromosomes. The absence of telomerase should have particularly significant consequences for stem cells, certain differentiated somatic cells, and the germline, as there are normally high levels of this enzyme activity in such cell types. In the absence of telomerase, repeat units at the ends of chromosomes are lost, leading to chromosomal abnormalities and exit from the cell cycle. The absence of the enzyme in most forms of replicating somatic cells is thought to be the major factor in replicative senescence. (more…)

Ataxia-telangiectasia is yet another example of a hutchinson gilford progeria syndrome caused by a deficiency of a gene product of central importance to the maintenance of genomic stability. Others could also be cited, permitting a generalization of what would seem to be intuitively obvious – namely, that an organism that has lost proficiency in maintaining the structure and function of its DNA will develop a pleiotropic set of signs and symptoms that only get worse during aging. These observations support the hypothesis that increasing genomic stability pays a major role in normative aging. (more…)