Claims of 'anti-ageing pill' may be premature

Abstract

The Daily Telegraph and Daily Express both carry headlines about how a “pill” to help humans live longer could be on the cards. Though while the substance being studied shows promise, the research only involved mice.

Researchers were looking at a chemical called SRT1720 which activates a particular protein called Sirtuin 1 (SIRT1). Previous research has demonstrated that activating SIRT1 can have health benefits in various organisms, and it has been proposed as an anti-ageing protein.

This study focused on comparing the lifespan, health and diseases of mice fed the same diet, but with or without the addition of a SRT1720. Overall they found mice fed a normal diet but with the supplement had a longer natural lifespan on average (about five weeks longer). During their lifetime, additional tests also suggested they had improved muscle function and coordination, improved metabolism, improved glucose tolerance, decreased body fat and cholesterol. All in all this suggests that giving the mice this supplement could protect them from the equivalent of metabolic syndrome, a series of risk factors associated with conditions such as heart disease and type 2 diabetes.

This is interesting research but as it only involved mice, the normal caveats regarding animal studies apply. Importantly, researchers did not look at whether SIRT1 may cause side effects or complications. So it is currently unclear whether SIRT1 would be safe in humans, let alone effective. The SIRT1 protein could be a possible candidate in the quest to find an “elixir of life” but these are very early days.

reposted from: http://www.nhs.uk/news/2014/02February/Pages/Claims-of-anti-ageing-pill-may-be-premature.aspx

crabsallover highlights, key points, comments / links.

Flu jab "may cut" stroke risk by a quarter

A recent report has revealed that people who have the seasonal flu jab are 24% less likely to suffer a stroke, according to The Daily Telegraph

The report is based on the results of a large study, which used the GP database for England and Wales to access data on almost 50,000 people who had suffered a stroke or transient ischaemic attack (TIA or a so-called “mini” stroke) over an eight-year period. Researchers then matched them to a person of the same age and gender who had attended the GP around the same time (these people are known as the “controls”). They then compared how likely they were to have been given the seasonal flu vaccine before the date of the stroke or TIA.

They found that slightly more controls had received the flu vaccine before the date: 50.8%, compared to 50.6% of people who had had a stroke or TIA. This meant that, overall, having the flu vaccine reduced the risk of a person having a stroke by about a quarter (there was no link with TIAs).

The research benefits from a large quantity of reliable data, with a number of health and lifestyle factors that may have influenced the results also adjusted.

It is plausible that a link exists between the protection against flu strains the vaccine provides and the risk of having a stroke.

The researchers summarise by saying they “reinforce current recommendations for annual influenza vaccination” with “potential added benefit for stroke prevention”.

Where did the story come from?

The study was carried out by researchers from the University of Lincoln and University of Nottingham, and was funded by the National Institute for Health Research.

The study was published in the peer reviewed journal Vaccine.

The Daily Telegraph and The Independent’s reporting of the study was accurate.

What kind of research was this?

This was a case-control study, which aimed to see if the influenza or pneumococcal vaccination might prevent a stroke. Some previous research studies have suggested that respiratory infections, such as the flu, may be associated with a stroke.

They cite a number of studies that have found there is an increased likelihood of respiratory symptoms in the weeks prior to having a stroke. However, other observational studies failed to find any significant link.

Due to this inconsistent evidence, the researchers aimed to investigate this further themselves, using data for thousands of people stored on the UK General Practice research database.

They identified people who had suffered a stroke or TIA and a matched group of people without, examining if they had been given the seasonal flu jab or the pneumococcal vaccine.

The pneumococcal vaccine is part of the child vaccination programme. It is also offered as a one-off jab to all adults over the age of 65 and to younger adults that have a heightened risk of infection (such as those with weakened immune systems). The vaccine protects them against infection with the bacteria Streptococcus pneumonia, which can cause pneumonia and other severe infections.

What did the research involve?

The researchers used the General Practice Research Database (now called the Clinical Practice Research Datalink, CPRD), which contains anonymised data for over 5% of the population of England and Wales. The database codes for vaccinations, diseases and health behaviours using a validated coding system. They used the eight-year period 2001-9 to identify adults coded for stroke or TIA (“case”). Each case was randomly matched to a control of the same age and gender who attended a general practice at the same time. They excluded cases and controls with a previous diagnosis of stroke or TIA.

They looked for vaccinations recorded prior to the ”index” date, when the stoke or TIA was recorded. Because the influenza vaccine is seasonal, the researchers looked to see if the vaccine was given in the same seasonal year (September 1 to August 31 the following year) and whether given “early” (between September 1 and November 15) or “late” (November 16 to February 28), and the time elapsed since last influenza vaccination (defined as 0 to 3, 3 to 6, 6 to 12, or more than 12 months before the index date). Pneumococcal vaccination was defined as vaccination at any time before the index date, as it is given as a one-off vaccine.

The researchers looked at the odds for cases and controls given either or both vaccines.

They adjusted their analyses for potential confounders, including cardiovascular risk factors, current medications, number of cormorbid medical illnesses, lifestyle factors (such as whether a person smokes) and the number of GP consultations and home visit requests. 

What were the basic results?

The researchers identified 47,011 cases (comprising 26,784 cases of stroke and 20,227 cases of TIA), with the same number of matched controls.

Very slightly more controls than cases had received the flu vaccine in the same season as the index date: 50.8% of controls compared to 50.6% of cases. After adjusting for the measured confounders, this meant that having an influenza vaccine within the same season as the index date was associated with a 24% reduction in the risk of a stroke (odds ratio [OR] 0.76, 95% confidence interval [CI] 0.72 to 0.80).

Further adjustment for body mass index (BMI), cholesterol and blood pressure slightly reduced the risk association, such that the risk reduction was only 19%, but still remained statistically significant(OR 0.81, 95% CI 0.77 to 0.85).

Reduction in the risk of a stroke was greatest when the vaccine had been given within three months of the index date (22% reduction), reducing to 11% reduced risk when the vaccine had been given between three and 12 months of the index date.

However, the flu vaccine only seemed to protect against a stroke if given early in the flu season: September to mid-November (26% risk reduction, OR 0.74, 95% CI 0.70 to 0.78). Giving the vaccine late in the flu season (mid-November to February) did not result in a significantly reduced risk.

Flu vaccine was not significantly associated with being at risk of TIA. Neither was pneumococcal vaccination significantly associated with being at risk of a stroke or TIA.

How did the researchers interpret the results?

The researchers conclude that: “Influenza vaccination was associated with a 24% reduction in risk of having a stroke, but not TIA. Pneumococcal vaccination was not associated with reduced risk of a stroke or TIA. This has important implications for the potential benefits of an influenza vaccine.”

Conclusion

This research finds that, overall, having the flu vaccine reduced the risk of a person experiencing a stroke by about 25%. The reduction in risk seemed to be greatest within the first three months of vaccination, but remained for up to 12 months.  However, the effect lasted only if the vaccine was given early in the flu season (September to mid-November); giving the vaccine late in the flu season (mid-November to February) was not associated with significantly reduced risk.

The research benefits from using data coded within the General Practice Research Database for England and Wales for almost 50,000 people with stroke or TIA, matched by age and gender to the same number of controls who had attended the GP at the same time. There is still potential for missing or miscoded information in the database, but overall the data is thought to be fairly reliable.

They also adjusted their analyses for a large number of potential confounders. The researchers say there is still the potential for what they call “healthy vaccine” bias, with healthier people more likely to be vaccinated, and are perhaps less likely to have a stroke.

The findings support previous studies, which the researchers say have suggested an association between recent respiratory illness and risk of a stroke; they have also studied findings that influenza vaccination may offer protection against another heart attacks. However, the biological mechanisms by which respiratory infections or influenza might precipitate cardiovascular events is unknown. It is also unknown if the findings could apply to younger people at risk.

In summary, it is plausible that there could be a link between the protection the flu vaccine gives against flu strains and a risk of suffering a stroke in the same season.

The purpose of the seasonal influenza vaccine is to protect against respiratory illness, not to offer possible protection against a stroke. However, the researchers “reinforce current recommendations for annual influenza vaccination” and that there is “the potential added benefit of stroke prevention”.

Even if the link between the flu jab and reduced stroke risk is unproven, it is always a good idea to get the jab if you are in one of the groups recommended to receive it. This is if you are:

• 65 years of age or over 
• pregnant
• have a long-term (chronic) medical condition such as asthma or diabetes
• living in a long-stay residential care home or other long-stay care facility
• receive a carer's allowance, or you are the main carer for an elderly or disabled person whose welfare may be at risk if you fall ill
• a healthcare worker with direct patient contact or a social care worker

Read more on who should get the flu jab.

Analysis by Bazian. Edited by NHS Choices. 

Follow Behind the Headlines on Twitter. 
Join the Healthy Evidence forum.

Links to the headlines

Flu jab could cut risk of stroke by quarter. The Daily Telegraph, February 20 2014

Winter flu jab may reduce stroke risk by up to a quarter. The Independent, February 20 2014

Links to the science

Siriwardena AN, Asghar Z, Coupland CA. Influenza and pneumococcal vaccination and risk of stroke or transient ischaemic attack—Matched case control study. Vaccine. Published online January 28 2014

reposted from: http://www.nhs.uk/news/2014/02February/Pages/Flu-jab-may-cut-stroke-risk-by-a-quarter.aspx

crabsallover highlights, key points, comments / links.

Lipid modification : Cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. NICE guideline: Draft for consultation, February 2014

reposted from: http://www.nice.org.uk/nicemedia/live/13637/66552/66552.pdf

(NB. full guidance: http://www.nice.org.uk/nicemedia/live/13637/66547/66547.pdf (not reviewed here))

My Key points (my highlights):-

• [1.3.16] Offer atorvastatin 20 mg for the primary prevention of CVD. [new 2014] 

• Use the QRISK2 risk assessment tool to assess CVD risk for the primary prevention of CVD. [new 2014] 
• Prioritise people for a full formal risk assessment if their estimated 10-year risk of CVD is 10% or more. [2008, amended 2014] 

• Use the QRISK2 risk assessment tool to assess CVD risk for the primary prevention of CVD. [new 2014] 
• Further information and advice on healthy cooking methods can be found at NHS Choices. [new 2014] 
• Before starting lipid modification therapy for the primary prevention of CVD, take at least 1 lipid sample to measure a full lipid profile. This should include measurement of total cholesterol, HDL cholesterol, non-HDL cholesterol, and triglyceride concentrations. A fasting sample is not needed. [new 2014] 
• Use the clinical findings, lipid profile and family history to judge the likelihood of a familial lipid disorder rather than the use of strict lipid cut-off values alone. [new 2014] 
• In this update the Guideline Development Group (GDG) recommend the use of non-high density lipoprotein (non-HDL) cholesterol rather than low density lipoprotein (LDL) cholesterol. LDL cholesterol is not directly measured but requires a calculation using a fasting sample and for triglyceride levels to be less than 4.5 mmol/litre, whereas the measurement of non-HDL does not. 
• Follow-up of people initiated on statin treatment 
• 1.3.29 Measure cholesterol, HDL cholesterol and non-HDL cholesterol in people who have been started on high-intensity statin treatment after 3 months of treatment and aim for a greater than 40% reduction in non-HDL cholesterol. If a greater than 40% reduction in non-HDL cholesterol is not achieved: 
• discuss adherence and timing of dose (take at night) 
• optimise adherence to diet and lifestyle measures 
• consider increasing dose if started on less than atorvastatin 80 mg and person is judged to be at higher risk because of comorbidities, risk score or using clinical judgement. [new 2014] 
• 1.3.38 Before offering a statin, ask the person if they have had persistent generalised unexplained muscle pain, whether associated or not with previous lipid-lowering therapy, and if present, measure creatine kinase levels. If these are elevated start statin treatment at a lower dose. [new 2014]
• 1.3.42 Measure baseline liver transaminase enzymes (alanine aminotransferase or aspartate aminotransferase) before starting a statin. Measure liver transaminase (alanine aminotransferase or aspartate aminotransferase) within 3 months of starting treatment and at 12 months, but not again unless clinically indicated. [2008, amended 2014] 
• 1.3.50 Tell people that there is no evidence that omega-3 fatty acid compounds help to prevent CVD. [new 2014] 
• Combination therapy for preventing CVD 
• 1.3.51 Do not offer the combination of a bile acid sequestrant (anion exchange resin), fibrate, nicotinic acid or omega-3 fatty acid compound with a statin for the prevention of CVD. [new 2014] 
• Appendix B: Grouping of statins 

For the purpose of this guideline, statins are grouped into 3 different intensity categories according to the percentage reduction in low-density lipoprotein cholesterol (see table 1). This grouping was agreed by GDG consensus, informed by analyses in the literature. See the full guideline for a discussion of this grouping. 

Reference

http://www.nice.org.uk/nicemedia/live/13637/66552/66552.pdf

Crabsallover Change in Statin Use

Switch from Simvastin 10mg/day = 27% reduction in low-density lipoprotein cholesterol, where low intensity = 20%-30%, to Atorvastatin 20mg/day = 43% high intensity (>40%). NB. Medium intensity (31%-40%)

NICE publishes new draft guidelines on statins use

crabsallover highlights, key points, comments / links.

"Millions more people should be put on cholesterol-lowering statin drugs," BBC News reports. Draft guidance from the National Institute for Health and Care Excellence (NICE) has recommended that the drugs should be given to people with an estimated 1 in 10 or more risk of cardiovascular disease (CVD), which includes conditions such as heart disease and stroke.

At present, guidance for doctors on using statins to prevent CVD says that only people with a 20% or greater risk of developing CVD in the next 10 years should be offered the drugs.

NICE recommends that a specific statin called atorvastatin is used for both the prevention and treatment of CVD.

How is CVD risk assessed?

NICE recommends a risk assessment tool called QRISK2. This involves a series of calculations based on the following factors:

• age
• sex
• body mass index (BMI)
• ethnicity
• family history of heart disease
• whether you have one or more of the following chronic diseases: diabetes, kidney disease, high blood pressure, atrial fibrillation or rheumatoid arthritis
• blood cholesterol levels
• your current blood pressure

Doctors should offer "high-intensity" treatment with statins to healthy people who have a 10% or greater 10-year risk of developing CVD. "High-intensity" statins produce the largest LDL reduction at the lowest doses.

Healthy patients at risk of CVD should be offered 20mg of a drug called atorvastatin to cut the risk of CVD. In the previous guidelines, therapy was started using 40mg of a drug called simvastatin. Atorvastatin is a high-intensity drug, while simvastatin is medium intensity.

Where do the draft guidelines come from?
The updated draft guidelines have been published by NICE, the National Institute for Health and Care Excellence. They are a draft update of the guidelines on lowering cholesterol (or lipid modification) that were published in 2008.
These are draft guidelines that have been published for consultation with professional and government organisations, patient and carer groups, and companies. These stakeholders have until March 26 2014 to comment before NICE decides on its final recommendations.
Anyone who wishes to comment on the guidelines must first register as a stakeholder. To find out more, visit the NICE consultation page.

What is the rationale behind the new recommendations?
The recommended changes have been made on the basis of cost effectiveness. For example, NICE concluded that high-intensity treatment with 20mg atorvastatin is more cost effective than statin treatment using medium-intensity simvastatin.
It also reports that medium-intensity treatment is more cost effective compared with no treatment or low-intensity treatment at all realistic risk levels.
The guideline group decided to change the threshold from 20% risk to 10% risk by taking into account "the uncertainty regarding the frequency of adverse events in routine clinical practice, which may be higher than in clinical trials, the uncertainty around the magnitude of the effectiveness of statins and the accuracy of the QRISK2 tool itself, as well as the base case cost effectiveness results and sensitivity analyses".
The drugs have become cheaper in recent years, and their effectiveness is well proven, NICE notes.

The organisation has also pointed out that although death rates from CVD have halved since the 1970s and 1980s, CVD is the cause of one in three deaths in the UK. At present, as many as seven million people in the UK are believed to be on statins, at an estimated annual cost of £450 million.

What are the risks of taking statins?
Statins can have side effects, although the most common ones, while a nuisance, are not serious. They include stomach upset, headache and insomnia. Occasionally, the drugs can cause inflammation and damage to the muscles. Serious side effects, such as jaundice and visual disturbance, are rare.
Statins are not suitable for everyone. For example, they should not be taken if you have severe liver disease or blood tests suggest your liver may not be working properly.
Read more about the side effects of statins.

What can I do to cut the risk of CVD?
As NICE makes clear, statins are not the only option for treating high cholesterol. Alternative treatments include eating a healthy diet that is low in saturated fats, increasing the amount of omega-3 fatty acids in your diet, and other prescribed medications.
Professor Mark Baker, director of the Centre for Clinical Practice at NICE, said: "As well as taking statins, people with raised cholesterol levels and high blood pressure should reduce the amount of foods containing saturated fat they eat.
"They should exercise more and control their blood glucose levels by reducing their intake of sugar and by losing weight. They should also stop smoking."

Read more advice about lowering your cholesterol levels.  

Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter. Join the Healthy Evidence forum.

Links to the headlines

Guidelines call for more people to be put on statins. BBC News, February 12 2014

Statins: 12 million Brits will be advised to take cholesterol-lowering drug. The Daily Telegraph, February 11 2014

'Millions' more to be prescribed statins to beat high cholesterol. The Independent, February 12 2014

One in four adults to be prescribed daily statin: Now patients with 10% heart attack risk will be offered drug. Mail Online, February 12 2014

Statins 'Should Be Offered To Millions More'. Sky News, February 12 2014

Cholesterol drug statins should be given to millions more, NHS guidance says. The Guardian, February 12 2014

Millions more to be given statins to ward off risk of stroke. Daily Express, February 12 2014

Millions more qualify for drugs to cut heart disease. The Times, February 12 2014

Further reading

National Institute for Health and Care Excellence. Lipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. February 2014

References
http://www.nhs.uk/news/2014/02February/Pages/NICE-publishes-new-draft-guidelines-on-statins-use.aspx (accessed 15th February 2014)

Another cell study spun as 'age-reversing miracle' - NAD+

reposted from: http://www.nhs.uk/news/2013/12December/Pages/Another-cell-study-spun-as-age-reversing-miracle.aspx

Links (accessed 26th December 2013)
http://en.wikipedia.org/wiki/Hypoxia-inducible_factors

Cell Journal
Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging http://www.cell.com/abstract/S0092-8674(13)01521-3#Summary

A New—and Reversible—Cause of Aging

A naturally produced compound rewinds aspects of age-related demise in mice

By DAVID CAMERON

December 19, 2013

Mitochondria, organelles on the right, interact with the cell's nucleus to ensure a healthy, functioning cell. Image by Ana Gomes

Researchers have discovered a cause of aging in mammals that may be reversible.

The essence of this finding is a series of molecular events that enable communication inside cells between the nucleus and mitochondria. As communication breaks down, aging accelerates. By administering a molecule naturally produced by the human body, scientists restored the communication network in older mice. Subsequent tissue samples showed key biological hallmarks that were comparable to those of much younger animals.

“The aging process we discovered is like a married couple—when they are young, they communicate well, but over time, living in close quarters for many years, communication breaks down,” said Harvard Medical School Professor of Genetics David Sinclair, senior author on the study. “And just like with a couple, restoring communication solved the problem.”

This study was a joint project between Harvard Medical School, the National Institute on Aging, and the University of New South Wales, Sydney, Australia, where Sinclair also holds a position.

The findings are published Dec. 19 in Cell.

Communication breakdown

Mitochondria are often referred to as the cell's "powerhouse," generating chemical energy to carry out essential biological functions. These self-contained organelles, which live inside our cells and house their own small genomes, have long been identified as key biological players in aging. As they become increasingly dysfunctional overtime, many age-related conditions such as Alzheimer’s disease and diabetes gradually set in.

Researchers have generally been skeptical of the idea that aging can be reversed, due mainly to the prevailing theory that age-related ills are the result of mutations in mitochondrial DNA—and mutations cannot be reversed.

Sinclair and his group have been studying the fundamental science of aging—which is broadly defined as the gradual decline in function with time—for many years, primarily focusing on a group of genes called sirtuins. Previous studies from his lab showed that one of these genes, SIRT1, was activated by the compound resveratrol, which is found in grapes, red wine and certain nuts.

Sirt1 protein, red, circles the cell's chromosomes, blue. Image by Ana GomesAna Gomes, a postdoctoral scientist in the Sinclair lab, had been studying mice in which thisSIRT1 gene had been removed. While they accurately predicted that these mice would show signs of aging, including mitochondrial dysfunction, the researchers were surprised to find that most mitochondrial proteins coming from the cell’s nucleus were at normal levels; only those encoded by the mitochondrial genome were reduced.

“This was at odds with what the literature suggested,” said Gomes.

As Gomes and her colleagues investigated potential causes for this, they discovered an intricate cascade of events that begins with a chemical called NAD and concludes with a key molecule that shuttles information and coordinates activities between the cell’s nuclear genome and the mitochondrial genome. Cells stay healthy as long as coordination between the genomes remains fluid. SIRT1’s role is intermediary, akin to a security guard; it assures that a meddlesome molecule called HIF-1 does not interfere with communication.

For reasons still unclear, as we age, levels of the initial chemical NAD decline. Without sufficient NAD, SIRT1 loses its ability to keep tabs on HIF-1. Levels of HIF-1 escalate and begin wreaking havoc on the otherwise smooth cross-genome communication. Over time, the research team found, this loss of communication reduces the cell's ability to make energy, and signs of aging and disease become apparent.

“This particular component of the aging process had never before been described,” said Gomes.

While the breakdown of this process causes a rapid decline in mitochondrial function, other signs of aging take longer to occur. Gomes found that by administering an endogenous compound that cells transform into NAD, she could repair the broken network and rapidly restore communication and mitochondrial function. If the compound was given early enough—prior to excessive mutation accumulation—within days, some aspects of the aging process could be reversed.

When Sirt1 loses its ability to monitor HIF-1, communication between mitochondria and the nucleus breaks down, and aging accelerates. Image by Ana Gomes

Cancer connection

Examining muscle from two-year-old mice that had been given the NAD-producing compound for just one week, the researchers looked for indicators of insulin resistance, inflammation and muscle wasting. In all three instances, tissue from the mice resembled that of six-month-old mice. In human years, this would be like a 60-year-old converting to a 20-year-old in these specific areas.

One particularly important aspect of this finding involvesHIF-1. More than just an intrusive molecule that foils communication, HIF-1 normally switches on when the body is deprived of oxygen. Otherwise, it remains silent. Cancer, however, is known to activate and hijack HIF-1. Researchers have been investigating the precise role HIF-1 plays in cancer growth.

“It’s certainly significant to find that a molecule that switches on in many cancers also switches on during aging,” said Gomes. “We're starting to see now that the physiology of cancer is in certain ways similar to the physiology of aging. Perhaps this can explain why the greatest risk of cancer is age.”

“There’s clearly much more work to be done here, but if these results stand, then certain aspects of aging may be reversible if caught early,” said Sinclair.

The researchers are now looking at the longer-term outcomes of the NAD-producing compound in mice and how it affects the mouse as a whole. They are also exploring whether the compound can be used to safely treat rare mitochondrial diseases or more common diseases such as Type 1 and Type 2 diabetes. Longer term, Sinclair plans to test if the compound will give mice a healthier, longer life.

The Sinclair lab is funded by the National Institute on Aging (NIA/NIH), the Glenn Foundation for Medical Research, the Juvenile Diabetes Research Foundation, the United Mitochondrial Disease Foundation and a gift from the Schulak family.

Press Release: http://hms.harvard.edu/news/genetics/new-reversible-cause-aging-12-19-13