Facts and Figures

• About 16.2 million Americans are now deeply affected by Alzheimer’s, 5.3 million who have the disease and another 10.9 million whose lives are wrapped up in caring for those who have the disease.

“In 2009, an estimated 10.9 million family members and friends provided unpaid care for a person with Alzheimer’s disease or another dementia.”  About 94 % of unpaid caregivers are family members; about 60% are women and about 60% are aged over 50.  The quality of the lives of many of these unpaid caregivers is seriously impacted by their caregiver responsibilities. 40% of caregivers of Alzheimer’s disease patients report high emotional stress compared to 28% of caregivers of other older people. “Because Alzheimer’s and other dementias usually progress slowly, most caregivers spend many years in the caregiving role. At any point in time, 32 percent of family and other unpaid caregivers of people with Alzheimer’s and other dementias have been providing help for five years or longer, including 12 percent who have been providing care for 10 years or longer. An additional 43 percent have been providing care for one to four years, and 23 percent have provided care for less than a year.”  (Quotes here are from the report)

• The total current economic impact of the disease is $316 billion, $172 of which is for paid care of those having the disease and $144 billion is for the effort of unpaid caregivers.  (Note that these figures do not take into account another very large amount for lost economic productivity of those having the disease.)

According to the report, payments for health and long-term care services for people with Alzheimer’s will total $172 billion this year. Unpaid caregivers provided 12.5 billion hours of care in 2009, valued at $144 billion with care valued at $11.50 per hour.  It is pointed out that this is more than the federal government spends on Medicare and Medicaid combined for people with Alzheimer’s and other dementias.

• More than any other disease, Alzheimer’s and other dementias are signature diseases of old age. Death rates rise precipitously with age.

Death rate per 100,000Age                

                         2000                 2006

45–54            0.2                        0.2

55–64            2.0                        2.1

65–74            18.7                   20.2

75–84            139.6               175.6

85+                  667.7              848.3 

Other diseases of old age do not present such a steep rise in the death rate with increasing age.  “To put such age-related differences into perspective, for U.S. deaths in 2006, the differences in total mortality rates from all causes of death for those aged 65–74 and those aged 75–84 was 2.5-fold, and between the 75–84 age group and the 85 and older age group, 2.6-fold. For diseases of the heart, the differences were 2.8-fold and 3.2-fold, respectively.  For all cancers, the differences were 1.7-fold and 1.3-fold respectively. The corresponding differences for Alzheimer’s were 8.7-fold and 4.8-fold.  This is because Alzheimer’s is most likely caused by cell senescence of microglia, increasing cell senescence being a normal consequence of the aging process.  Getting Alzheimer’s is part of normal aging.  It is not necessarily caused by a bacterium or virus and does not necessarily require a gene defect although it could be triggered by such conditions.

·        There is currently no treatment for the disease 

“No treatment is available to slow or stop the deterioration of brain cells in Alzheimer’s disease. The U.S. Food and Drug Administration has approved five drugs that temporarily slow worsening of symptoms for about six to 12 months, on average, for about half of the individuals who take them.”  Puny results for expensive drugs is all the pharmaceutical industry has been able to provide at this point. 

·        While the risk of death due to other diseases continues to decrease with time, the risk of death due to Alzheimer’s disease is rapidly increasing. 

Between 3000 and 2006 causes of death % changes:

Alzheimer’s disease           +46.1%

Stroke                                    -18.2%

Prostate cancer                    -8.7%          

Heart disease                       -11.1%

HIV                                         -16.3%

The report projects 500,000 new cases of Alzheimer’s will be diagnosed this year. The report estimates that almost a million new cases of Alzheimer’s will be diagnosed annually by 2050.

• Medicare costs for Alzheimer’s patients are almost three times higher than for other older people and Medicaid costs are almost nine times higher.

“Hospital: In 2004, Medicare beneficiaries aged 65 and older with Alzheimer’s and other dementias were 3.1 times more likely than other Medicare beneficiaries in the same age group to have a hospital stay.  – Skilled nursing facility: In 2004, Medicare beneficiaries aged 65 and older with Alzheimer’s and other dementias were eight times more likely than other Medicare beneficiaries in the same age group to have a Medicare-covered stay in a skilled nursing facility.”

• The disease affects women more than men and blacks and Hispanics more than whites.
  • Blacks are roughly twice as likely to get the disease compared to whites.
  • Hispanics  are roughly 1.5 times as likely to get the disease compared to whites.
  • Women are more or less 1.7 times or more likely to get the disease then men, depending on the age group.
• Alzheimer disease patients are likely to have concurrent medical issues

Percentage withAlzheimer’s or OtherDementia and theCoexisting Condition       

Hypertension                                                    60%

Coronary heart disease                                  26%

Stroke—late effects                                         25%

Diabetes                                                             23%

Osteoporosis                                                     18%

Congestive heart failure                                16%

Chronic obstructive pulmonary disease     15%

Cancer                                                                 13%

Parkinson’s disease                                            8%

Data is for 2004 medicare beneficiaries aged 65 and older

What more can be done about Alzheimer’s disease?

I would like to see a few things shifted.

1.     I think it would be beneficial to stop viewing Alzheimer’s disease as yet another disease we are seeking to cure and start viewing AD as intrinsically wrapped up with aging, one of several aging processes that gets ahead of the other aging processes in AD patients.  The present find-a-specific-cure viewpoint has not worked and can’t work because AD is due to cell senescence of microglia. It is due to a process that is intrinsic to aging itself.  In fact, if we could delay all other age-related diseases, then AD would get virtually everybody by age 125.  In other words, curing AD and “curing aging” are likely to be part and parcel of the same thing.

2.     Major shifts in AD research are in order.  Efforts to find a chemical by trial-and-error that is a partial or entire cure, such as pharmaceutical companies have been pursuing for decades, are a modern form of alchemy rather than scientific research.  Any research that is going to move us forward has to look at the fundamental molecular biological and genetic-genomic processes involved. 

3.     I suspect that current research and clinical trials aimed at reducing or eliminating tau tangles and amyloid-beta plaques in AD patients(ref) may lead to therapies that slow the progress of AD but are unlikely to produce cures because they do not address the root cause of the disease.

4.     I think the research cited in the blog entry New views of Alzheimer’s disease and new approaches to treating it points its fingers at microglial cell senescence as a root cause for AD.  Additional research I have reviewed since writing that blog entry confirms this conclusion.  Therefore, any treatment that fundamentally addresses AD must address cell senescence and/or failure of cell replacement through stem cell differentiation.  If a treatment works to significantly delay or prevent AD it is likely to work to significantly delay or prevent many other diseases and processes of aging as well.  The answer may lie in a more effective form of telomerase activation(ref), in reversing epigenomic markers of aging such as DNA methylation at selected promoter sites(ref) or in manipulating the stem cell supply chain probably using induced pluripotent stem cells(ref) or embryonic stem cells(ref).  Perhaps activation of the BDNF gene could be involved(ref).  Those are the kinds of basic research that should be encouraged.

5.     Another shift in aging and Alzheimer’s research is that there should be lots more of it. The report says “for every $25,000 the government spends on care for people with Alzheimer’s and dementia, it spends only $100 for Alzheimer research.”  This is an order-of-magnitude too little.

6.     Finally it is important to reiterate that a number of approaches are available to ordinary people that can usually delay onset of Alzheimer’s disease, other forms of dementia and other diseases resulting from cell senescence.  These are the measures in the anti-aging firewalls in my treatise ANTI-AGING FIREWALLS THE SCIENCE AND TECHNOLOGY OF LONGEVITY.  Many of my blog entries are also relevant such as Warding off Alzheimer’s Disease and things in my diet and Seven Ps of health and longevity.  And a search of blog entries using the term dementia will turn up several additional relevant blog entries.

Vitamin D and the VDR

Vitamin D is mentioned several times in my treatise and is a central pillar of the combined anti-aging firewalls Supplement Regimen.    I have also discussed or mentioned it in many` blog posts.  The post Vitamin D - don’t fall for it  describes research on how vitamin D administration in nursing communities significantly reduces the number of falls and consequent hip fractures and other orthopedic injuries.  The blog post Klotho anti-aging gene in the news describes how “Klotho expression is also important for averting premature aging due to overexpression of Vitamin D,” citing a number of papers relevant to that topic.  And the post Hypervitaminosis D and premature aging indicates, among other topics, how mice with their VDR gene knocked out age prematurely.  “The publication Premature aging in vitamin D receptor mutant mice  (vitamin D receptor (VDR) knockout mice)  states “Overall, VDR KO mice showed several aging related phenotypes, including poorer survival, early alopecia, thickened skin, enlarged sebaceous glands and development of epidermal cysts.”  “Since the phenotype of aged VDR knockout mice is similar to mouse models with hypervitaminosis D(3), our study suggests that VDR genetic ablation promotes premature aging in mice, and that vitamin D(3) homeostasis regulates physiological aging.”

Vitamin D3 (1alpha,25-dihydroxyvitamin D) is the active form of vitamin D taken in supplements and is of concern in this post.  It functions as a hormone.  D3 is also known as calcitriol.  A growing body of research publications point to the health importance of D3 in numerous biological pathways that go beyond bone health.  I cite only two as examples.  According to the 2008 publication The noncalciotropic actions of vitamin D: recent clinical developments, “RECENT FINDINGS: 1,25-Dihydroxyvitamin D stimulates the innate immune system, facilitating the clearance of infections such as tuberculosis. Hypovitaminosis D has been associated with several autoimmune disorders, various malignancies, and cardiovascular risk factors in a number of recent epidemiologic reports. Based on these observational reports, vitamin D and its analogues are being evaluated for the prevention and treatment of a variety of conditions, with early findings showing mixed results. SUMMARY: The broad tissue distribution of the 25-hydroxyvitamin D 1alpha-hydroxylase enzyme and the vitamin D receptor establish a role for 1,25-dihydroxyvitamin D in the pathophysiology of various disease states and provide new therapeutic targets for vitamin D and its analogues.”

A 2007 publication Expanding role for vitamin D in chronic kidney disease: importance of blood 25-OH-D levels and extra-renal 1alpha-hydroxylase in the classical and nonclassical actions of 1alpha,25-dihydroxy vitamin D(3) reports “Recent advances in the understanding of vitamin D have revolutionized our view of this old nutritional factor and suggested that it has much wider effects on the body than ever believed before. In addition to its well-known effects on calcium/phosphate homeostasis, vitamin D, through its hormonal form, 1alpha,25-dihydroxyvitamin D(3) or calcitriol, is a cell differentiating factor and anti-proliferative agent with actions on a variety of tissues around the body (e.g., skin, muscle, immune system). By influencing gene expression in multiple tissues, calcitriol influences many physiological processes besides calcium/phosphate homeostasis including muscle and keratinocyte differentiation, insulin secretion, blood pressure regulation, and the immune response. The incidence of various diseases including epithelial cancers, multiple sclerosis, muscle weakness as well as bone-related disorders has been correlated with vitamin D deficiency/insufficiency and has led to a re-evaluation of recommended daily intakes both in the normal subject and CKD patient.”

Even back in the early 2000s it was clear that D3 was important for the functioning of the immune system, but how and why was unclear.  The 2004 publication Vitamin D status, 1,25-dihydroxyvitamin D3, and the immune system  reported “The active form of vitamin D, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], has been shown to inhibit the development of autoimmune diseases, including inflammatory bowel disease (IBD). Paradoxically, other immune system-mediated diseases (experimental asthma) and immunity to infectious organisms were unaffected by 1,25(OH)2D3 treatment. There are similar paradoxical effects of vitamin D deficiency on various immune system functions. Vitamin D and vitamin D receptor (VDR) deficiency resulted in accelerated IBD.

”The vitamin D3 receptor (VDR) gene generates a protein which is a transcription factor that is activated by the presence of D3. “The calcitriol receptor, also known as the vitamin D receptor (VDR) and also known as NR1I1 (nuclear receptor subfamily 1, group I, member 1), is a member of the nuclear receptor family of transcription factors.^[1] Upon activation by vitamin D, the VDR forms a heterodimer with the retinoid-X receptor and binds to hormone response elements on DNA resulting in expression or transrepression of specific geneproducts. In humans, the vitamin D receptor is encoded by the VDR gene.^[2]”  Exploration of the activities of VDR has been key to discovering the various roles of vitamin D3 in maintaining health.

Vitamin D3 in the immune response

The new 7 March 2010 publication Vitamin D controls T cell antigen receptor signaling and activation of human T cells reports an important finding - Presence of vitamin D3 in the bloodstream is required for T cells being activated and mounting an effective immune response.  As reported yesterday in Science Daily: “For T cells to detect and kill foreign pathogens such as clumps of bacteria or viruses, the cells must first be ‘triggered’ into action and ‘transform’ from inactive and harmless immune cells into killer cells that are primed to seek out and destroy all traces of a foreign pathogen. — The researchers found that the T cells rely on vitamin D in order to activate and they would remain dormant, ‘naïve’ to the possibility of threat if vitamin D is lacking in the blood.”  The sequence of events is “First when the naive T cell recognizes foreign invaders like bacteria or viruses with T cell receptor (TCR), it sends activating signals - to the vitamin D receptor gene. The VDR gene then starts producing DVR protein, which binds vitamin D in the T cell - and becomes activated. Then the vitamin D bound and activated DVR gets into the cell nucleus and activates the gene for PLC-gamma1 (5), which in turn produces PLC-gamma1 protein - and “the T cells can get started(ref).””

““Professor Carsten Geisler from the Department of International Health, Immunology and Microbiology explains that “when a T cell is exposed to a foreign pathogen, it extends a signaling device or ‘antenna’ known as a vitamin D receptor, with which it searches for vitamin D. This means that the T cell must have vitamin D or activation of the cell will cease. If the T cells cannot find enough vitamin D in the blood, they won’t even begin to mobilize. ” — T cells that are successfully activated transform into one of two types of immune cell. They either become killer cells that will attack and destroy all cells carrying traces of a foreign pathogen or they become helper cells that assist the immune system in acquiring “memory”. The helper cells send messages to the immune system, passing on knowledge about the pathogen so that the immune system can recognize and remember it at their next encounter. T cells form part of the adaptive immune system, which means that they function by teaching the immune system to recognize and adapt to constantly changing threats(ref).”

Implications

The new finding can explain a lot of the protective effects of D3,  ranging from reducing susceptibility to colds and flu(ref) to the role of D3 in chronic kidney disease(ref), reducing risk of asthma and respiratory infections(ref), its role in Graves’ hyperthyroidism(ref), how it fights placental infection(ref), bacterial vaginosis(ref) and pediatric infections(ref), and its protective effects against many other infections too numerous to catalog here.  And of course, vitamin D is essential for prevention and control of cardiovascular diseases(ref).  Unless someone is out in the sunlight for sustained periods every day, vitamin D3 supplementation is an absolute health necessity.

Please note the medical disclaimer for this blog.

About sestrins

Sestrins are small protein molecules produced by three evolutionary conserved  genes in mammals, of which the sesn1 and sesn2 genes are activated by the p53 tumor-suppressor gene(ref)(ref).  Normally, when oxidative or other forms of stress activate p53, the target sesn1 and sesn2 genes are activated in turn.  These genes in turn activate AMP-dependent protein kinase (AMPK), which serves to inhibit  the Target of Rapamycin. E.g. inhibit  mTOR signaling(ref). Sestrins also provide a level of antioxidant defense in cells(ref). The 2007 publication p53 Target Genes Sestrin1 and Sestrin2 Connect Genotoxic Stress and mTOR Signaling provides ample detail for those of you who may wish to dig deeper.

Sestrins and longevity

The actions of sestrins are interesting from the viewpoint of longevity because for some time it has been known that inhibiton of mTOR signaling can lead to longer lifespans.  See the earlier blog post More mTOR links to aging theories “In my May 2009 blog post Longevity genes, mTOR and lifespan, I discussed the mTOR signaling pathway in mammals, its role in diseases, the relationship of mTOR to mitochondrial activity and how inhibiting mTOR could conceivably be a strategy for extending longevity.  In my Anti-Aging Firewalls treatise I subsequently added ABERRANT mTOR SIGNALLING as one of six additional candidate theories of aging to be considered.” See also the blog entry Viva mTOR! Caveat mTOR!.  Note that the m in mTOR stands for mammalian.“

The role of AMPK in regulating cellular energy charge places this enzyme at a central control point in maintaining energy homeostasis. More recent evidence has shown that AMPK activity can also be regulated by physiological stimuli, independent of the energy charge of the cell, including hormones and nutrients(ref).”  Exercise can increase AMPK activity as can taking certain polyphenol supplements like resveratrol(ref).  Another of the conditions that can activate AMPK is calorie restriction, a condition that slows down aging.  On the other hand, over-nutrition activates mTOR, accelerating aging.

The latest result appeared in the March 5 issue of Science: Sestrin as a Feedback Inhibitor of TOR That Prevents Age-Related Pathologies.  “We show that the abundance of Drosophila sestrin (dSesn) is increased upon chronic TOR activation through accumulation of reactive oxygen species that cause activation of c-Jun amino-terminal kinase and transcription factor Forkhead box O (FoxO).  Loss of dSesn resulted in age-associated pathologies including triglyceride accumulation, mitochondrial dysfunction, muscle degeneration, and cardiac malfunction, which were prevented by pharmacological activation of AMPK or inhibition of TOR. Hence, dSesn appears to be a negative feedback regulator of TOR that integrates metabolic and stress inputs and prevents pathologies caused by chronic TOR activation that may result from diminished autophagic clearance of damaged mitochondria, protein aggregates, or lipids.”  In other words, if TOR gets ramped up, in the absence of genetic damage it turns on sestrin which ramps TOR down again before TOR activity creates major damage.

According to a Science Daily article about this latest research, “They also showed that Sestrin, whose structure and biochemical function are conserved between flies and humans, is needed for regulation of a signaling pathway that is the central controller of aging and metabolism. – The new study took advantage of the finding that the fruit fly Drosophila, whose AMPK-TOR signaling pathway functions in the same manner as its mammalian equivalent, contains a single Sestrin gene. Using a variety of genetic techniques, first author Jun Hee Lee inactivated the Sestrin gene of Drosophila and found that although Sestrin-deficient flies do not exhibit any developmental abnormalities, they suffer from under-activation of AMPK and over-activation of TOR — confirming that Sestrin is needed for keeping this pathway in check. Most importantly, the biochemical imbalance incurred by loss of Sestrin expression resulted in several age-related pathologies. — “Strikingly, the pathologies caused by the Sestrin deficiency included accumulation of triglycerides, cardiac arrhythmia and muscle degeneration that occurred in rather young flies,” said Karin. “These pathologies are amazingly similar to the major disorders of overweight, heart failure and muscle loss that accompany aging in humans.” — Lee and colleagues at UC San Diego and the Sanford-Burnham Institute in La Jolla, California, went on to demonstrate that feeding flies with drugs that either activate AMPK or inhibit TOR conferred protection against most of these early aging, degenerative symptoms. The researchers also found that over-activation of TOR is likely to accelerate aging of heart and skeletal muscles by disrupting an important “quality control” process called autophagy. Autophagy allows cells to rid themselves of and replace damaged mitochondria, the little power plants that provide all cells, especially muscles, with energy. However, when mitochondria get old, they produce high concentrations of reactive oxygen species (ROS), or free radicals, that can lead to tissue damage.”

I have previously discussed how an effective antiaging intervention might be inhibition of mTOR.  The new research goes on to say how this might be accomplished through activation of sestrins. 

Sestrins and cancer

In many cancers, oncogenic mutations in RAS genes result in inactivation of p53 genes and resulting failure of activation of sestrin genes which results in increased  ROS (reactive oxygen species) levels and further oncogenic mutations.  This scenario is depicted in the 2007 paper Repression of Sestrin Family Genes Contributes to Oncogenic Ras-Induced Reactive Oxygen Species Up-regulation and Genetic Instability.  “Oncogenic mutations within RAS genes and inactivation of p53 are the most common events in cancer. Earlier, we reported that activated Ras contributes to chromosome instability, especially in p53-deficient cells. — Introduction of oncogenic RAS resulted in repression of transcription from sestrin family genes SESN1 and SESN3, which encode antioxidant modulators of peroxiredoxins. Inhibition of mRNAs from these genes in control cells by RNA interference substantially increased ROS levels and mutagenesis. — Thus, changes in expression of sestrins can represent an important determinant of genetic instability in neoplastic cells showing simultaneous dysfunctions of Ras and p53.”

About BDNF

“BDNF acts on certain neurons of the central nervous system and the peripheral nervous system, helping to support the survival of existing neurons, and encourage the growth and differentiation of new neurons and synapses.^[4][5] In the brain, it is active in the hippocampus, cortex, and basal forebrain—areas vital to learning, memory, and higher thinking.^[6] BDNF itself is important for long-term memory(ref).^[7] ”  BDNF is an important neurotrophic, meaning that it plays an important role in neurogenesis, the important process in parts of the brain of neural stem cells differentiating into neurons. “Neurotrophins are a family of proteins that induce the survival,^[1] development and function^[2] of neurons. — Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor found originally in the brain, but also found in the periphery. More specifically, it is a protein which has activity on certain neurons of the central nervous system and the peripheral nervous system; it helps to support the survival of existing neurons, and encourage the growth and differentiation of new neurons and synapses through axonal and dendritic sprouting. In the brain, it is active in the hippocampus, cortex, cerebellum, and basal forebrain—areas vital to learning, memory, and higher thinking. BDNF was the second neurotrophic factor to be characterized, after NGF and before neurotrophin-3. — Despite its name, BDNF is actually found in a range of tissue and cell types, not just the brain. Expression can be seen in the retina, the CNS, motor neurons, the kidneys, and the prostate(ref).”

BDNF and mental balance

According to the December 30 2009 paper BDNF Val66Met is Associated with Introversion and Interacts with 5-HTTLPR to Influence Neuroticism. “Brain-derived neurotrophic factor (BDNF) regulates synaptic plasticity and neurotransmission, and has been linked to neuroticism, a major risk factor for psychiatric disorders. A recent genome-wide association (GWA) scan, however, found the BDNF Val66Met polymorphism (rs6265) associated with extraversion but not with neuroticism. — ). Consistent with GWA results, we found that BDNF Met carriers were more introverted. — Our findings support the association between the BDNF Met variant and introversion and suggest that BDNF interacts with the serotonin transporter gene to influence neuroticism.” 

Also, aberrant BDNF is implicated in memory loss, anxiety and schizophrenia. Again, the culprit gene variant seems to be Val66met.  According to the 2008 publication Impact of genetic variant BDNF (Val66Met) on brain structure and function, “A common single-nucleotide polymorphism in the human brain-derived neurotrophic factor (BDNF) gene, a methionine (Met) substitution for valine (Val) at codon 66 (Val66Met) — A genetic variant BDNF may thus play a key role in genetic predispositions to anxiety and depressive disorders.”   Another relevant 2008 research publication is Meta-Analysis of the Brain-Derived Neurotrophic Factor (BDNF} Val66Met Polymorphism in Anxiety Disorders and Anxiety-Related Personality Traits.

Research study after research study have pointed to the importance of healthy expression of BDNF for long term memory including BDNF: A Key Regulator for Protein-synthesis Dependent LTP and Long-term Memory? and Regulation of late-phase LTP and long-term memory in normal and aging hippocampus: role of secreted proteins tPA and BDNF.

The association of BDNF VAL66Met with mental issues has been known for several years now.  According to the 2005 publication Association of a functional BDNF polymorphism and anxiety-related personality traits “Converging lines of evidence point to brain-derived neurotrophic factor (BDNF) as a factor in the pathophysiology of depression. Recently, it was shown that the Val allele of the BDNF Val66Met substitution polymorphism showed a significant association with higher mean neuroticism scores of the NEO-Five Factor Inventory (NEO-FFI) in healthy subjects, and previous studies suggested the Val allele to be increased in bipolar disorder families. — Our findings support the hypothesis that anxiety- and depression-related personality traits are associated with the BDNF polymorphism although the explained variance is low.”

Going back even a bit further, according to a 2003 NIMH research press release “NIH scientists have shown that a common gene variant influences memory for events in humans by altering a growth factor in the brain’s memory hub. On average, people with a particular version of the gene that codes for brain derived neurotrophic factor (BDNF) performed worse on tests of episodic memory—tasks like recalling what happened yesterday. They also showed differences in activation of the hippocampus, a brain area known to mediate memory, and signs of decreased neuronal health and interconnections. These effects are likely traceable to limited movement and secretion of BDNF within cells, according to the study, which reveals how a gene affects the normal range of human memory, and confirms that BDNF affects human hippocampal function much as it does animals’(ref).” 

The BDNF dementia and aging connection

Expression of BDNF is implicated in aging.  The 2008 study report Genetic contributions to age-related decline in executive function: a 10-year longitudinal study of COMT and BDNF polymorphisms says “Our results argue that — the Val/Val polymorphism for BDNF may promote faster rates of cognitive decay in old age. These results are discussed in relation to the role of BDNF in senescence and the transforming impact of the Met allele on cognitive function in old age.”

In fact expression of BDNF is implicated in anti-aging.   According to a news item published yesterday “UC Irvine neurobiologists are providing the first visual evidence that learning promotes brain health – and, therefore, that mental stimulation could limit the debilitating effects of aging on memory and the mind. Using a novel visualization technique they devised to study memory, a research team led by Lulu Chen and Christine Gall found that everyday forms of learning animate neuron receptors that help keep brain cells functioning at optimum levels. — These receptors are activated by a protein called brain-derived neurotrophic factor, which facilitates the growth and differentiation of the connections, or synapses, responsible for communication among neurons. BDNF is key in the formation of memories.” — “The findings confirm a critical relationship between learning and brain growth and point to ways we can amplify that relationship through possible future treatments,” says Chen, a graduate researcher in anatomy & neurobiology.”  I have reported previously in this blog on the importance of mental exercise and learning for prevention of dementia and longevity.  See the blog posts Mental exercise and dementia in the news again and Brain fitness, Google and comprehending longevity.  The new finding highlights the key role of BDNF expression in the process. 

I mentioned research on the use of neural stem cells as a source of BDNF in the blog entry Human embryonic stem cells and Alzheimer’s disease quoting the 2009 research report Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease. “Additionally, the improvement in memory and the increase in synaptic density observed after injection of neural stem cells were found to be mediated, at least in part, by the neurotrophic factor BDNF, which is secreted from the transplanted cells. GRNOPC1 has been found to secrete BDNF as well as other neurotrophic factors(ref).”  “Taken together, our findings demonstrate that neural stem cells can ameliorate complex behavioral deficits associated with widespread Alzheimer disease pathology via BDNF(ref).”

The BDNF epigenetics connection – DNA methylation and chromatin remodeling

Recent studies have gone beyond looking at the Val66Met polymorphism to identifying another reason for unwanted downregulation of BDNF expression – BDNF gene promoter methylation.  The 2010 paper Increased BDNF Promoter Methylation in the Wernicke Area of Suicide Subjects points to downregulation of BDNF activity due to DNA methylation being observed in suicide subjects.  The paper reports: Context  Brain-derived neurotrophic factor (BDNF) plays a pivotal role in the pathophysiology of suicidal behavior and BDNF levels are decreased in the brain and plasma of suicide subjects. So far, the mechanisms leading to downregulation of BDNF expression are poorly understood.  Objectives  To test the hypothesis that alterations of DNA methylation could be involved in the dysregulation of BDNF gene expression in the brain of suicide subjects.  Design  Three independent quantitative methylation techniques were performed on postmortem samples of brain tissue. BDNF messenger RNA levels were determined by quantitative real-time polymerase chain reaction. ^–. Main Outcome Measures  The DNA methylation degree at BDNF promoter IV and the genome-wide DNA methylation levels in the brain’s Wernicke area. Results  Postmortem brain samples from suicide subjects showed a statistically significant increase of DNA methylation at specific CpG sites in BDNF promoter/exon IV compared with nonsuicide control subjects (P < .001). —  Higher methylation degree corresponded to lower BDNF messenger RNA levels.  Conclusions  BDNF promoter/exon IV is frequently hypermethylated in the Wernicke area of the postmortem brain of suicide subjects irrespective of genome-wide methylation levels, indicating that a gene-specific increase in DNA methylation could cause or contribute to the downregulation of BDNF expression in suicide subjects. The reported data reveal a novel link between epigenetic alteration in the brain and suicidal behavior.”  It is tempting to hypothesize that BDNF methylation is a causal factor in suicides but the paper does not go that far.

The 2008 paper Epigenetic regulation of BDNF gene transcription in the consolidation of fear memory reports: Long-term memory formation requires selective changes in gene expression. Here, we determined the contribution of chromatin remodeling to learning-induced changes in brain-derived neurotrophic factor (bdnf) gene expression in the adult hippocampus. Contextual fear learning induced differential regulation of exon-specific bdnf mRNAs (I, IV, VI, IX) that was associated with changes in bdnf DNA methylation and altered local chromatin structure. — altered DNA methylation is sufficient to drive differential bdnf transcript regulation in the hippocampus — .  These results suggest epigenetic modification of the bdnf gene as a mechanism for isoform-specific gene readout during memory consolidation.”

Going back a bit earlier there was the 2005 paper Regional expression of brain derived neurotrophic factor (BDNF) is correlated with dynamic patterns of promoter methylation in the developing mouse forebrain. “These studies demonstrate that DNA methylation of this regulatory region may be an important mechanism controlling differential expression of BDNF during forebrain development.”

Early-life experiences or experiences of parents or grandparents can create changes in BDNF DNA methylation which affect learning, attitude or mental stability, as pointed out in the 2009 publication Lasting Epigenetic Influence of Early-Life Adversity on the BDNF Gene.  “Background: Childhood maltreatment and early trauma leave lasting imprints on neural mechanisms of cognition and emotion. With a rat model of infant maltreatment by a caregiver, we investigated whether early-life adversity leaves lasting epigenetic marks at the brain-derived neurotrophic factor (BDNF) gene in the central nervous system.  Methods: During the first postnatal week, we exposed infant rats to stressed caretakers that predominately displayed abusive behaviors. We then assessed DNA methylation patterns and gene expression throughout the life span as well as DNA methylation patterns in the next generation of infants.  Results: Early maltreatment produced persisting changes in methylation of BDNF DNA that caused altered BDNF gene expression in the adult prefrontal cortex. Furthermore, we observed altered BDNF DNA methylation in offspring of females that had previously experienced the maltreatment regimen.  Conclusions: These results highlight an epigenetic molecular mechanism potentially underlying lifelong and transgenerational perpetuation of changes in gene expression and behavior incited by early abuse and neglect.”

Putting it together

There are many more relevant BDNF literature citations out there, but these are sufficient to make certain key points:

·        Healthy BDNF gene expression is important for mental health, learning, memory, and preservation of cognitive capability with aging

·        One thing that can get in the way of healthy BDNF gene expression is the Val66Met polymorphism in the BDNF gene, a genetic condition.

·        Another thing that can get in the way of healthy BDNF gene expression is gene methylation, a type of epigenetic modification that can be induced by experience and that is possibly inheritable.  We have all known that early experience shapes the character.  We now know that one way that shaping takes place is molecularly via methylation of the BDNF gene.

·        Certain stem cells like those in Geron’s proprietary hESC-based GRNOPC1 line secrete BDNF and offer one means for introducing BDNF expression into tissues.

Repair mechanisims for double-strand breaks in DNA

In the course of a normal good day you may have a million or more events of DNA damage occur in your body.  If you are exposed to ionizing radiation or any substance that creates large numbers of free radicals or if you have certain disease processes like Alzheimer’s going on, the number of DNA damage events could be many times higher.  The kinds of DNA damage can be of multiple types(ref).  In this blog entry I am concerned with one particular important kind, double-strand breaks (DSBs), breaks that can occur naturally in cell differentiation or that are created by radiation and certain chemicals.   “The current view is that most spontaneous chromosomal rearrangements result from DSBs created mainly during DNA replication as a result of broken, stalled or collapsed replication forks(ref).”  

Because these breaks completely threaten genomic integrity, evolution has provided us with a number of sophisticated approaches for automatic DNA repair.  See Dancing on damaged chromatin: functions of ATM and the RAD50/MRE11/NBS1 complex in cellular responses to DNA damage.  “In order to preserve and protect genetic information, eukaryotic cells have developed a signaling or communications network to help the cell respond to DNA damage, and ATM and NBS1 are key players in this network. ATM is a protein kinase which is activated immediately after a DNA double strand break (DSB) is formed, and the resulting signal cascade generated in response to cellular DSBs is regulated by post-translational protein modifications such as phosphorylation and acetylation. In addition, to ensure the efficient functioning of DNA repair and cell cycle checkpoints, the highly ordered structure of eukaryotic chromatin must be appropriately altered to permit access of repair-related factors to DNA. These alterations are termed chromatin remodeling.”

Failure to repair double-strand DNA breaks or faulty repairs can have serious consequences.  As pointed out in the review publication Misrepair of radiation-induced DNA double-strand breaks and its relevance for tumorigenesis and cancer treatment:  “The faithful repair of DNA double-strand breaks (DSBs) is probably one of the most critical tasks for a cell in order to maintain its genomic integrity since these lesions may lead to chromosome breaks or rearrangements, mutations, cell death or cancer. DSBs can arise spontaneously during normal cellular DNA metabolism or may be induced by exogenous agents such as ionizing radiation. To overcome the danger that emanates from these lesions, eukaryotic cells have evolved specific pathways for processing DSBs. —  ”  Moreover, it is thought that an impaired capacity to repair double-strand breaks can lead to chromosome Instability (CIN) “ — a genome phenotype that involves changes in chromosome number or structure, and accounts for most malignancies(ref).”

There are two general repair pathways for double strand breaks, homologous recombination (HR) and non-homologous end joining (NHEJ). “Defects in either repair pathway result in high frequencies of genomic instability[4]. The HR pathway utilizes a homologous sequence to faithfully restore the DNA continuity at the DSB[5]. In contrast, NHEJ is a mechanism able to join DNA ends with no or minimal homology [6] (ref).”  “Non-homologous DNA end-joining (NHEJ)–the main pathway for repairing double-stranded DNA breaks–functions throughout the cell cycle to repair such lesions. Defects in NHEJ result in marked sensitivity to ionizing radiation and ablation of lymphocytes, which rely on NHEJ to complete the rearrangement of antigen-receptor genes. NHEJ is typically imprecise, a characteristic that is useful for immune diversification in lymphocytes, but which might also contribute to some of the genetic changes that underlie cancer and ageing(ref).”

The DNA repair pathways are complex but one gene/protein important both to faithful cell division and DNA repair appears to be Mms22, studied originally in budding yeast strains(ref)(ref). 

Roles of proteasomes in repairing double-strand DNA breaks

I found the new February 2010 publication Proteasome Nuclear Activity Affects Chromosome Stability by Controlling the Turnover of Mms22, a Protein Important for DNA Repair to be difficult to decipher at first.  So, I need to proceed slowly here.   Proteasomes are tiny protein recycling factories that live in cells, either in the cytoplasm or in the nucleus.  Actually they are sizeable protein complexes shaped like drums that breakup unneeded proteins (ones that are damaged, misfolded or used for short-term purposes as part of cell maintenance) using a chemical process called proteolysis.  “The degradation process yields peptides of about seven to eight amino acids long, which can then be further degraded into amino acids and used in synthesizing new proteins.^[2] Proteins are tagged for degradation with a considerably small protein called ubiquitin.  – The proteasomal degradation pathway is essential for many cellular processes, including the cell cycle, the regulation of gene expression, and responses to oxidative stress(ref).” 

For a long time is was thought that  DNA duplication and repair had nothing to do with the proteasomes, nothing anymore than an effective pressure cooker has to do with a garbage dispose-all.  The new research says “not so.”  In fact, DNA repair might not be completed because of defects in proteasome machinery. 

The new publication cites impressive research indicating that what goes on when a double-strand DNA break occurs includes 1.  Mms22 gets attracted to the double break site where it does its repair job.  2.  In the process Mms22 also gets highly ubiquinated, e.g. several morsels of ubiquitin are attached to it and thus it becomes a target for proteasomal degradation, 3.  Certain proteasomes (“The 26S proteasome comprises the 20S core particle (CP) and the 19S regulatory particle (RP), which represent the base and lid substructures, respectively(ref).”) are also attracted to the DNA break site, probably by accumulated ubiquinated Mms22, where they capture and set out to degrade the Mms22.  4.  If degradation is successful the DNA repair is completed, and 5.  If degradation is not successful the DNA break repair is not completed and the cell goes into prolonged cell-cycle arrest. 

“Indeed, we show that DNA damage results in Mms22 recruitment to the chromatin bound fraction –. Importantly, our results also show that recruitment of Mms22 to chromatin is not sufficient for the normal course of DNA repair, and that an essential step is a proteasome-mediated degradation of Mms22. These results thus identify for the first time a proteasome target that links proteasomal nuclear activity and DNA double strand break repair(ref).”  Also, “In this regard, proteasome inhibition in combination with DNA damage probably results in the accumulation of many proteins besides Mms22, which altogether may lead to the impaired recovery from the cell cycle arrest(ref).”The authors of the paper put it this way: “DNA damage results in a SCFrtt101 E3 ubiquitin ligase-dependent accumulation of the ubiquitinated form of Mms22 on chromatin that, as suggested above, plays a role in dealing with DNA damage. Subsequent degradation of ubiquitinated Mms22 by the proteasome is an important step in completion of the DNA repair process. Once Mms22 executes its function in DNA repair it becomes a target for degradation by the UPS (ubiquitin proteasome system), and is removed from chromatin.  Failure to degrade Mms22 results in impaired DNA repair and prolonged cell cycle arrest(ref).”

The authors point the finger for failure in double strand repair (and consequently for chromosome instability and carcinogenesis) to defects in the proteasomes: “In our current work, we show that mutations in the proteasome subunits rpn5ΔC and pup2, which cause nuclear mislocalization, are associated with impaired DSB (double-strand break) repair. All other proteasomal Ts mutants tested were sensitive to drugs inducing DSBs, implying that the proteolytic activity of the proteasome is required for DNA repair(ref).”  As mentioned, the mutations can cause the proteasomes of concern to locate outside of the cell nucleus where they normally reside making them unavailable to ubiquinated Mms22.

The research work described was done using strains of yeast (Saccharomyces cerevisiae) but is thought to be applicable to humans because of orthologs between human and yeast genes(ref)(ref).   

What I take away from this research is:

·        What we have here is another case of what was thought to be a well-understood cell component (a proteasome) showing up with a brand new function and importance. 

 ·        It provides another chunk of understand about important cell processes, another piece of the giant jigsaw puzzle that will eventually make clear to us what aging is and what we can do about it.  See my blog post The longevity jigsaw puzzle.

·        With each new piece of the puzzle, it seems that more questions are raised than are answered.  In the case of the research described above some of the questions are: Do these results largely based on yeast studies completely carry over to apply to humans?   If so, what can be done about defects in the genes for the proteasome subunits rpn5ΔC and pup2 to help prevent cancers?  Do proteasomes play a similar role with other DNA repair genes besides Mms22? What other interventions might be suggested by this work to improve efficiency of repair of double-strand DNA breaks?

·        There is a lot more interesting research related to DNA repair beyond the thread covered here and I will probably come back to that topic again before too long. 

In case you have forgotten, “Alzheimer’s disease is a neurodegenerative disorder that represents the most important cause of dementia in humans. Extracellular deposits of β-amyloid peptides (Aβ), often termed senile plaques, and formation of intracellular neurofibrillary tangles of hyperphosphorylated tau protein are the two principal hallmarks of this disease. Aβ aggregates are known to induce synaptic dysfunction, and thus are linked with learning and memory deficits in both human and mouse models of the disease, making Aβ deposits a target for prevention or treatment(ref).” 

Microglia are intimately involved in the maintenance of normal brain functioning and in the etiology of many neurodegenerative conditions, including AD.  “Microglia are a type of glial cells that are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the central nervous system (CNS). Microglia constitute 20% of the total glial cell population within the brain.^] Microglia (and astrocytes) are distributed in large non-overlapping regions throughout the brain and spinal cord.^[1][2] Microglia are constantly excavating the CNS for damaged neurons, plaques, and infectious agents(ref).^[3]”

One role of microglia, that of amplifying pain, was introduced in the blog post Spinal cord injury pain.  There have been various theories as to the involvement of microglia in AD including a very interesting new one.  Physically, “Microglia are attracted to Aβ aggregates and decorate plaques. Such a phenomenon has been observed in both human and transgenic mouse model of Alzheimer’s disease, suggesting an important role for these cells in the CNS(ref).” 

AD, microglia and cellular senescence

Over less than a decade there has been a 180 degree shift from seeing microglial activation as a main cause of AD to seeing microglial senescence as a main cause of AD.

The 2009 study Telomeres Acquire Embryonic Stem Cell Characteristics in Induced Pluripotent Stem Cells was important in that it showed that reversion of cells to iPSC status fully restores telomerase activity to iPSCs, equivalent to that in embryonic stem cells (ESCs). “We show here that telomeres are elongated in iPS cells compared to the parental differentiated cells both when using four (Oct3/4, Sox2, Klf4, cMyc) or three (Oct3/4, Sox2, Klf4) reprogramming factors and both from young and aged individuals.  We demonstrate genetically that, during reprogramming, telomere elongation is usually mediated by telomerase and that iPS telomeres acquire the epigenetic marks of ES cells, including a low density of trimethylated histones H3K9 and H4K20 and increased abundance of telomere transcripts. Finally, reprogramming efficiency of cells derived from increasing generations of telomerase-deficient mice shows a dramatic decrease in iPS cell efficiency, a defect that is restored by telomerase reintroduction.”  Further, the 2009 publication Balancing Out the Ends during iPSC Nuclear Reprogramming discusses how “telomere length maintenance and long-term proliferative capacity of iPSCs is dependent on telomerase,” and concludes “Although a number of hurdles must still be cleared before iPS-based cell therapy becomes practical, the results (cited above) suggest that reprogramming of telomerase and telomeres may not be one them.”

The new this-week finding provides evidence that reverting cells to induced iPSC status fully restores their ability to express telomerase, even in a case when the original cells are seriously compromised in terms of telomere maintenance capability.  The 17 February 2010 online publication Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients states “Patients with dyskeratosis congenita (DC), a disorder of telomere maintenance, suffer degeneration of multiple tissues^{1, 2, 3}. Patient-specific induced pluripotent stem (iPS) cells⁴ represent invaluable in vitro models for human degenerative disorders like DC. A cardinal feature of iPS cells is acquisition of indefinite self-renewal capacity, which is accompanied by induction of the telomerase reverse transcriptase gene (TERT)^{5, 6, 7}. We investigated whether defects in telomerase function would limit derivation and maintenance of iPS cells from patients with DC. Here we show that reprogrammed DC cells overcome a critical limitation in telomerase RNA component (TERC) levels to restore telomere maintenance and self-renewal. We discovered that TERC upregulation is a feature of the pluripotent state, that several telomerase components are targeted by pluripotency-associated transcription factors, and that in autosomal dominant DC, transcriptional silencing accompanies a 3′ deletion at the TERC locus. Our results demonstrate that reprogramming restores telomere elongation in DC cells despite genetic lesions affecting telomerase, and show that strategies to increase TERC expression may be therapeutically beneficial in DC patients.” 

Dyskeratosis congenita (DC) “is a rare progressive congenital disorder which results in what in some ways resembles premature aging (similar to progeria). — Specifically, the disease is related to one or more mutations which directly or indirectly affect the vertebrate telomerase RNA component (TERC).”  Apparently several different telomerase-related mutations can lead to DC  - see ref and the associated list of citations.  A 2008 publication Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita explains “Most of the mutations so far identified in patients with classical dyskeratosis congenita impact either directly or indirectly on the stability of RNAs. In keeping with this effect, patients with dyskerin, NOP10, and now NHP2 mutations have all been shown to have low levels of telomerase RNA in their peripheral blood, providing direct evidence of their role in telomere maintenance in humans.”   

The amazing thing about the latest study is that activities of two of the four new genes introduced during cell reprogramming appear to override the effect of the mutated gene or genes that defines the genetic defect that causes DC.  The reverted iPS cells appear to be capable of expressing telomerase and reproducing indefinitely, unlike the original DC cells which cannot express telomerase and die after a few generations.    

The iPSCs generated from DC patients continue to have the mutated genes that created the DC disease.  In fact, they should be like the patient’s original ESCs.  Therefore, there is no guarantee that cells those iPSCs differentiate into will have a capability to express telomerase; I suspect they won’t.  If the iPSCs are going to be used as a therapy for DC, they should be corrected first by splicing out the mutated genes and replacing them with good ones.  See the blog post Treating genetic diseases with corrected induced pluripotent stem cells. 

Besides possibly opening the way to a new therapy for DC, the finding provides further evidence that iPSCs could possibly close the loop in the stem cell supply chain enabling extraordinarily long lives.  See the blog post The stem cell supply chain – closing the loop for very long lives. The essence of the Stem Cell Supply Chain Breakdown theory of aging is that with aging the various pools of somatic (adult) stem cells in the body become depleted and those adult stem cells that are left are less prone to differentiate.  I am talking about mesenchymal and hematopoietic stem cells among others.  Adult stem cells like all other cells are differentiated from our original embryonic stem cells (ESCs).  Unlike ESCs or iPSCs, however, the adult stem cells express less telomerase and have limited replicative lifespans.  The result is that tissue renewal via replacement of normal tissue cells with differentiated somatic stem cells declines with age leading to the symptoms of aging.  So, I have speculated that if we can take a few normal body cells, revert them to iPSC status, multiply them in culture, correct them genetically if necessary,  and then re-introduce them into our bodies so they differentiate to replace the somatic stem cells in their niches, we could create cell renewal that is now a once-through (open loop) process that runs down with age into a continuously operating (closed loop) process that might go a long way towards eliminating aging.  The new finding confirms that reverting cells to iPSC status also gets them off to a roaring start generating telomerase just like ESCs do, and can do that even when the original cells have broken telomerase-generating genes in the case of DC. 

The idea of greatly enhancing longevity by closing the loop in the stem cell supply chain is of course a theory.  We will not know if it will work until it is tried.  The challenges that have to be overcome appear to be 1.  Reverting cells to iPSC status in substantial quantities and in ways that do not introduce foreign genes such as genes from a virus vector into the cell’s DNA, 2. Correcting the DNA in iPSCs for any mutational defects as pointed out above, and 3.  Introducing the iPSCs into the body in such a way that they differentiate in a controlled manner into somatic stem cells in the respective adult stem cell niches.  There has been significant progress on the first challenge as reported in the blog posts Footprint-free” iPSCs – and a crazy wager offer, Update on induced pluripotent stem cells, and Progress in closing the stem cell supply chain loop.  We appear to be moving along but much remains to be learned, particularly regarding the third challenge.

I have already created a number of blog entries reporting on GWAS studies.  My focus here is on the general characteristics of GWAS studies, why they are important, why we will see more and more on them, and where they will lead us.

GWAS studies and why they are important

Except for a minor cold now or then, Ann never gets sick. She has a very positive attitude towards life and seems never to experience stress.  Ann was born in a small mining town in Iowa and spent her youth there.  She Moved to Des Moines at about 19, and then later to Detroit, to a 90-acre farm in Yale Michigan, and then to New York.   Ann tells me that when she was about 11 she came across copies of a now long-defunct Macfadden health magazine which strongly influenced her to have healthy eating habits.  She mostly avoids junk food.   Ann takes no medicines. She started taking a multivitamin pill and fish oil only this year.  Other than that she has taken no supplements.   

So, speaking as somebody who has seen many doctors and takes many supplements, I do infer a few things about longevity from the example of Ann. 

1.     Ann must be a winner in the longevity genetic luck-of-the-draw.  Her mother lived to 96 and her maternal grandmother to 92.  On the other hand all seven of her siblings have passed away, and all were younger than Ann.   Her genome must contain a good pro-longevity combination of genes.  I think I could convince Ann to let her genome be sequenced if I could find a reputable longevity-oriented genetics researcher interested in finding out what is keeping her going.

2.     Ann is aging significantly more slowly than many of us.  The rate of aging is not the same for everybody.  Many people are run-down, sick and old at 50 or 60.  Ann is in good physical and mental shape and at 92 probably has a number of years still to go in good health.  Of course, I personally want and would love that.

3.     Ann’s longevity and health has nothing to do with medical progress or getting good medical advice or taking the latest drugs.  She has steered clear of those things all her life. 

4.     Longevity implies not getting the diseases of old age, not managing them, not curing them once you get them.  The same genetic activation pathways that lead to long lives keep us healthy.  This appears to be a lesson learned by researchers at the Kenyon Lab at the University of California, the people who did some of the original research on extending the lifespan of nematodes. “Our work has now led to the discovery that mammalian aging is also regulated hormonally by insulin and IGF-1 endocrine system and has catalyzed a fundamental shift in the way scientists view the aging process, from one that is inevitable and intractable to one that is plastic and subject to regulation. Our findings have important disease implications, since these long-lived mutants have been found to be resistant to many age-related diseases. This raises the possibility of a new therapeutic strategy based on the ability to postpone the onset of age-related disease by slowing the aging process itself(ref).”

5.     Successful aging might mean a lot fewer encounters with the medical establishment because a lot fewer sickness will come up.  Successful anti-aging strategies might make us like Ann.  Instead of senior citizens requiring 3-5 medical appointments a week, a yearly checkup might do.  Most medical practice is repair-shop in nature, dealing with managing or curing sicknesses that have emerged.  If sicknesses emerge a lot less, the need for doctors or hospitals recedes in importance. So, some people on a successful anti-aging track may develop the same attitude as Ann.  “Who needs a Doctor?”

6.     The annual health-care cost for Ann is zero.  Her medicare cost is zero.  If we could all extend our healthy lifespans by ten years it would be worth about ten trillion dollars in decreased health care costs and perhaps twice that much more in productivity gains. (Current US health care costs are something like 3 trillion dollars representing over 17% of gross domestic product(ref), and a disproportionally large slice of the cost is for people in the last 10 years of their lives.)

Longevity is by far the best area of investment for economic development.  With an increase of 10 years in our average healthy lifespan, we could quickly wipe out both the national budget deficit and the national debt.