Sirt1 Regulates Proliferation and Regeneration of Glial Progenitor Cells After Injury

Summary: A new study reports Sirt1 can help glial cells to regenerate from progenitor cells in preterm babies with hypoxia related injuries.

Source: Children’s National Health System.

Preemie brains hold specialized cells in reserve that can repair brain injury suffered early in life.

Developing brains in newborns have a sizable pool of a certain type of immature progenitor cell that can be expanded and induced to replace cells lost to brain injury. In a pre-clinical model of premature brain injury, the sirtuin protein Sirt1 plays a crucial role in regenerating glial cells from endogenous progenitor cells after hypoxia-related brain injury suffered by preemies, a research team led by Children’s National Health System reports December 19 in Nature Communications.

“It is not a cure. But, in order to regenerate the white matter that is lost or damaged, the first steps are to identify endogenous cells capable of regenerating lost cells and then to expand their pool. The glial progenitor cells represent 4 to 5 percent of total brain cells,” says Vittorio Gallo, Ph.D., Director of the Center for Neuroscience Research at Children’s National, and senior author of the study. “It’s a sizable pool, considering that the brain is made up of billions of cells. The advantage is that these progenitor cells are already there, with no requirement to slip them through the blood-brain barrier. Eventually they will differentiate into oligodendrocyte cells in white matter, mature glia, and that’s exactly what we want them to do.”

The study team identified Sirt1 as a novel, major regulator of basal oligodendrocyte progenitor cell (OPC) proliferation and regeneration in response to hypoxia in neonatal white matter, Gallo and co-authors write. “We demonstrate that Sirt1 deacetylates and activates Cdk2, a kinase which controls OPC expansion. We also elucidate the mechanism by which Sirt1 targets other individual members of the Cdk2 signaling pathway, by regulating their deacetylation, complex formation and E2F1 release, molecular events which drive Cdk2-mediated OPC proliferation,” says Li-Jin Chew, Ph.D., Research Associate Professor at Children’s Center for Neuroscience Research and a study co-author.

Hypoxia-induced brain injury in neonates initiates spontaneous amplification of progenitor cells but also causes a deficiency of mature oligodendrocytes. Inhibiting Sirt1 expression in vitro and in vivo showed that loss of its deacetylase activity prevents OPC proliferation in hypoxia while promoting oligodendrocyte maturation – which underscores the importance of Sirt1 activity in maintaining the delicate balance between these two processes.

The tantalizing findings – the result of four years of research work in mouse models of neonatal hypoxia – hint at the prospect of lessening the severity of developmental delays experienced by the majority of preemies, Gallo adds. About 1 in 10 infants born in the United States are delivered preterm, prior to the 37th gestational week of pregnancy, according to the Centers for Disease Control and Prevention. Brain injury associated with preterm birth – including white matter injury – can have long-term cognitive and behavioral consequences, with more than 50 percent of infants who survive prematurity needing special education, behavioral intervention and pharmacological treatment, Gallo says.

Time is of the essence, since Sirt1 plays a beneficial role at a certain place (white matter) and at a specific time (while the immature brain continues to develop). “We see maximal Sirt1 expression and activity within the first week after neonatal brain injury. There is a very narrow window in which to harness the stimulus that amplifies the progenitor cell population and target this particular molecule for repair,” he says.

Image shows a preterm baby.

Sirt1, a nicotinamide adenine dinucleotide-dependent class III histone deacetylase, is known to be involved in normal cell development, aging, inflammatory responses, energy metabolism and calorie restriction, the study team reports. Its activity can be modulated by sirtinol, an off-the-shelf drug that inhibits sirtuin proteins. The finding points to the potential for therapeutic interventions for diffuse white matter injury in neonates.

Next, the research team aims to study these processes in a large animal model whose brains are structurally, anatomically and metabolically similar to the human brain.

“Ideally, we want to be able to promote the timely regeneration of cells that are lost by designing strategies for interventions that synchronize these cellular events to a common and successful end,” Gallo says.

ABOUT THIS NEUROSCIENCE RESEARCH ARTICLE

Source: Dee Henderson – Children’s National Health System
Image Source: NeuroscienceNews.com image is credited to Children’s National Health System.
Original Research: Full open access research for “Sirt1 regulates glial progenitor proliferation and regeneration in white matter after neonatal brain injury” by Beata Jablonska, Marcin Gierdalski, Li-Jin Chew, Teresa Hawley, Mackenzie Catron, Arturo Lichauco, Juan Cabrera-Luque, Tracy Yuen, David Rowitch & Vittorio Gallo in Nature Communications. Published online December 19 2016 doi:10.1038/ncomms13866


Abstract

Sirt1 regulates glial progenitor proliferation and regeneration in white matter after neonatal brain injury

Regenerative processes in brain pathologies require the production of distinct neural cell populations from endogenous progenitor cells. We have previously demonstrated that oligodendrocyte progenitor cell (OPC) proliferation is crucial for oligodendrocyte (OL) regeneration in a mouse model of neonatal hypoxia (HX) that reproduces diffuse white matter injury (DWMI) of premature infants. Here we identify the histone deacetylase Sirt1 as a Cdk2 regulator in OPC proliferation and response to HX. HX enhances Sirt1 and Sirt1/Cdk2 complex formation through HIF1α activation. Sirt1 deacetylates retinoblastoma (Rb) in the Rb/E2F1 complex, leading to dissociation of E2F1 and enhanced OPC proliferation. Sirt1 knockdown in culture and its targeted ablation in vivo suppresses basal and HX-induced OPC proliferation. Inhibition of Sirt1 also promotes OPC differentiation after HX. Our results indicate that Sirt1 is an essential regulator of OPC proliferation and OL regeneration after neonatal brain injury. Therefore, enhancing Sirt1 activity may promote OL recovery after DWMI.

“Sirt1 regulates glial progenitor proliferation and regeneration in white matter after neonatal brain injury” by Beata Jablonska, Marcin Gierdalski, Li-Jin Chew, Teresa Hawley, Mackenzie Catron, Arturo Lichauco, Juan Cabrera-Luque, Tracy Yuen, David Rowitch & Vittorio Gallo in Nature Communications. Published online December 19 2016 doi:10.1038/ncomms13866

How to avoid a recession

There are several things  to try and avoid recession. Basically, the government and monetary authorities need to try and increase  aggregate demand (consumer spending, investment, exports). There is no guarantee that they will work. It will depend on the policies and also the causes of the recession.

For example, it is easier if the downturn affects just one country. In a global downturn, you are more subject to the fate of economies.

If the recession is caused by very high interest rates, then cutting interest rates may help avoid a recession. But, if you have a large fall in asset prices / bank losses (often called balance sheet recession) it is more difficult because even if you cut interest rates, banks may still not lend.

Policies to avoid a Recession

1. Cutting Interest Rates.  Cutting interest rates should help to boost aggregate demand. Amongst other things, lower interest rates reduce mortgage interest payments, giving consumers more disposable income. Lower interest rates also encourage firms and consumers to spend rather than save. (effect of lower interest rates)

As well as cutting base rates, the monetary authorities could try and reduce other interest rates in the economy. e.g. the Central Bank could buy government bonds or mortgage securities. Buying these bonds causes lower interest rates and helps to boost spending in the economy.

However, lower interest rates don’t always work. In 2008- 09, interest rates were cut to 0.5% in the UK, yet it didn’t avoid a recession. This was because

  • Banks didn’t pass the base rate cut onto consumers
  • Although interest rates were low, banks were reluctant to lend and consumers reluctant to spend.
  • This is known as a liquidity trap

In 2011, there is the prospect of a second recession, but interest rates are already low. Therefore, in this case it is not helpful.

2. Preventing Home repossessions. Home repossessions can cause bank losses and falls in consumer spending. The government may try to freeze mortgage rates to preventing house repossession. (e.g. Effects of Freezing subprime rates )Also, the Federal Reserve

3. Expansionary Fiscal Policy.  Cutting taxes increases consumer disposable income. This can be a policy to increase consumer spending. However, it will cause higher government borrowing. This may not be practical for countries who are already seeing a rise in government bond yields (e.g. Euro members like Greece, Ireland and Italy, have little scope for expansionary fiscal policy)

Also, there is no guarantee tax cuts will boost spending if confidence is very low.  Can tax cuts avoid a recession?

As well as tax cuts, the government could try higher government spending on capital investment projects. This directly injects money into the economy, it may be more effective than tax cuts, if tax cuts are just saved.
4. Devaluation. A devaluation in the exchange rate can cause a boost in aggregate demand. A fall in the value of the dollar, makes exports cheaper and imports more expensive increasing domestic demand. (see: effects of devaluation)

However, in a global recession, demand for exports may be quite inelastic. Also, in a global recession, countries may begin competitive devaluation. This is when several countries try to gain a competitive advantage by devaluing currency against others, but it proves self-defeating.

5. Quantitative Easing If interest rates are already zero, then the Central Bank may have to pursue unconventional monetary policies. This involves the Central Bank electronically creating money and using this money to buy long dated securities. This increases bank reserves and should help encourage bank lending. Also, it reduces interest rates on bonds which should help encourage spending and investment. See: Quantitative Easing explained

6. Higher Inflation Target. This is a conscious decision to target growth rather than inflation.  See: Optimal inflation target

Indexed Annuity contributions are part of the distribution process in retirement

Index Annuities Gains

In 2008, the SP500 lost about 40% of its value.  Investors in indexed annuities did not lose a cent which took nearly 4 years for the SP500 to get back to 2007 levels.

For individuals who were retiring in 2008, or had tax qualified accounts in an Indexed annuity and passed away, that was a great deal.   Some use an indexed annuity as the “safe” portion of a portfolio as an asset class

Fees

Most indexed annuities have “$0” fees and $0 admin and maint. fees. An estimated 95% of indexed annuities have zero fees associated with their policies unless you add a specific rider for income or death benefit guarantees.  That commission is paid to the agent from the company, it doesn’t come out of the clients portfolio.

Many agents take their commission over a 5 year period, meaning that their commission is <1% annually, which is less than most brokerage account manager’s charge.

Surrender charges

State regulators limit the surrender charges. The highest surrender charge that I can find is 14% in year one (two financial companies), and that is only available in a few states.   Surrender charges in annuities function very similar to Bank CD surrender charges.  If you pull the investment before maturity, you will pay a penalty.   That is why it is called a “contract”.

There is built in liquidity that every policy has by state law.  Usually this amount is 10% annually, and some companies allow that 10% to aggregate (i.e.  if you don’t pull funds for 5 years, you can pull up to 50% of the contract in one withdraw without penalty).

 Taxes

Taxes are the same as any 401k, IRA, or qualified plan (the same thing that the author recommends in the final section).   Suitability practices over the past five to ten years or so have increased substantially to prevent mis-representation by agents or the companies.

 Personalized client investment goals

Not every client is trying to maximize return, some simply want the guarantee that they won’t lose any of their principal, their taxes are deferred, and don’t mind if it’s in a 5- 10 year contract with minimum guarantees.   There are very few annuities that have flexible premiums and allow annual contributions, most are single premium rollovers.   Putting money into an indexed annuity or an ongoing contribution strategies are part of the “Accumulation” process leading to retirement.

Email Connie at motherhealth@gmail.com or conniedbuono@gmail.com to have a chat with a sr investment advisor to help you reduce your income taxes and protect your cash flow. 408-854-1883

Where to fit Voya’s Fixed Index Annuity in your diversified asset base

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Fixed Index Annuity

Now you have an option to accumulate your money outside of the bank CDs.  At age 40plus, you want a stronger vehicle with protection of principal and growth up to 5% with no market risks.

vs Bank CD

Contact Connie Dello Buono for a Fixed index annuity that is favorable than the bank CDs. 408-854-1883 motherhealth@gmail.com or conniedbuono@gmail.com

 

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Email Connie at motherhealth@gmail.com to track your miles and awards programs. Call Connie 408-854-1883 to have your own The Living Balance Sheet which includes tracking of your miles and awards programs and most of all 30min access for . And include your time to learn how to use it with an LBS expert at our office.