January 03, 2012
Mitochondrial Aging Especially Important In Stem Cells?

Mitochondria are sub-cellular organelles that break down sugar to make energy for the cell. Our mitochondrial DNA accumulate mutations and mitochondria become less functional as a result. Possibly other mechanisms are at working causing mitochondrial aging as well. A new report finds mitochondrial damage accumulation in stem cells has an especially large impact on overall aging.

Aging-related tissue degeneration can be caused by mitochondrial dysfunction in tissue stem cells. The research group of Professor Anu Suomalainen Wartiovaara in Helsinki University, with their collaborators in Max Planck Institute for Biology of Aging, Karolinska Institutet and University of Wisconsin reported on the 3rd January in Cell Metabolism their results on mechanisms of aging-associated degeneration.

Stem cells are called the spare parts for tissues, as they maintain and repair tissues during life. They are multipotent and can produce a variety of different cell types, from blood cells to neurons and skin cells. Mitochondria are the cellular engine: they transform the energy of nutrients to a form that cells can use, and in this process they burn most of the inhaled oxygen. If this nutrient 'burning' is inefficient, the engine will produce exhaust fumes, oxygen radicals, which damage cellular structures, including the genome. Antioxidants target to scavenge these radicals.

Already in 2004 and 2005 a research model was created in Sweden and USA, which accumulated a heavy load of mitochondrial genome defects. This led to symptoms of premature aging: thin skin, graying of hair, baldness, osteoporosis and anemia.

In the current publication, scientist Kati Ahlqvist in Professor Suomalainen Wartiovaara's group showed that these symptoms were partially explained by stem cell dysfunction. The number of stem cells did not reduce, but their function was modified: the progeny cells in blood and the nervous system were dysfunctional. The researchers also found out that these defects could be partially prevented by early antioxidant treatment.

Stem cells are needed to create replacements for damaged cells that die off or cease to do their jobs. Damaged stem cells are unable to perform their function. So less repair gets done as our stem cells accumulate damage and become dysfunctional with age. Biotechnology that would enable us to replace our old stem cells with younger ones would go far to slow and partially reverse aging.

Another research team found that in mice bred to age rapidly stem cell injections slowed aging and enabled the mice to live longer.

PITTSBURGH, Jan. 3 – Mice bred to age too quickly seemed to have sipped from the fountain of youth after scientists at the University of Pittsburgh School of Medicine injected them with stem cell-like progenitor cells derived from the muscle of young, healthy animals. Instead of becoming infirm and dying early as untreated mice did, animals that got the stem/progenitor cells improved their health and lived two to three times longer than expected, according to findings published in the Jan. 3 edition of Nature Communications.

Previous research has revealed stem cell dysfunction, such as poor replication and differentiation, in a variety of tissues in old age, but it's not been clear whether that loss of function contributed to the aging process or was a result of it, explained senior investigators Johnny Huard, Ph.D., and Laura Niedernhofer, M.D., Ph.D. Dr. Huard is professor in the Departments of Orthopaedic Surgery and of Microbiology and Molecular Genetics, Pitt School of Medicine, and director of the Stem Cell Research Center at Pitt and Children's Hospital of PIttsburgh of UPMC. Dr. Niedernhofer is associate professor in Pitt's Department of Microbiology and Molecular Genetics and the University of Pittsburgh Cancer Institute (UPCI).

"Our experiments showed that mice that have progeria, a disorder of premature aging, were healthier and lived longer after an injection of stem cells from young, healthy animals," Dr. Niedernhofer said. "That tells us that stem cell dysfunction is a cause of the changes we see with aging."

Stem cells from young healthy mice enabled progeria mice (i.e. mice selected for to age more rapidly) to live longer.

Their team examined a stem/progenitor cell population derived from the muscle of progeria mice and found that compared to those from normal rodents, the cells were fewer in number, did not replicate as often, didn't differentiate as readily into specialized cells and were impaired in their ability to regenerate damaged muscle. The same defects were discovered in the stem/progenitor cells isolated from very old mice.

"We wanted to see if we could rescue these rapidly aging animals, so we injected stem/progenitor cells from young, healthy mice into the abdomens of 17-day-old progeria mice," Dr. Huard said. "Typically the progeria mice die at around 21 to 28 days of age, but the treated animals lived far longer – some even lived beyond 66 days. They also were in better general health."

The symptoms which old mice suffer from serve as a reminder of why we need rejuvenation therapies. Do you want to hunch over, tremble, or move slowly and awkwardly? I think not.

As the progeria mice age, they lose muscle mass in their hind limbs, hunch over, tremble, and move slowly and awkwardly. Affected mice that got a shot of stem cells just before showing the first signs of aging were more like normal mice, and they grew almost as large. Closer examination showed new blood vessel growth in the brain and muscle, even though the stem/progenitor cells weren't detected in those tissues.

Once rejuvenating stem cell therapies become available I expect people will start using them while still at fairly young ages. Starting in one's 20s doesn't seem too soon.

Share |      Randall Parker, 2012 January 03 10:18 PM  Aging Mechanisms


Comments
Dan said at January 4, 2012 10:59 AM:

It seems like there should be a way to encase mitochondria in viral sheaths and inject them into ageing cells...

Randall Parker said at January 4, 2012 6:11 PM:

Dan,

They are too big for that. We should eventually be able to deliver DNA updates though.

There's another alternative: Get the cells with damaged mitochondria to kill themselves. Do this gradually as youthful cells are introduced to take their place. It is a tricky thing since in many cases a damaged cell is better than no cell. Selective killing by cell type would reduce the risks. For example, a topical application that kills old skin cells would be less risky than something that might kill something crucial like, say, heart nerve cells.

I think there's a big benefit to be had from killing off old immune system cells to make room for more effective younger immune cells.

Lou Pagnucco said at January 5, 2012 10:16 AM:

I believe this was discussed in an earlier FuturePundit posting, but it is worth revisiting the finding that quercetin increases numbers of mitochondria in muscle and the brain:

"Quercetin increases brain and muscle mitochondrial biogenesis and exercise tolerance"
http://ajpregu.physiology.org/content/296/4/R1071.long

I am not sure what the drawbacks to quercetin consumption are, but maybe defective mitochondria are more apt to be removed when new ones are available as replacenments?


mark l. said at January 5, 2012 11:24 AM:

good to see mitochondria getting attention...

the connection in (some) breast cancer following a maternal line, is consistent with the fact that mitchondria is always inherited from the mother. my pet theory is that the role of mitochondria, broadly described as producing energy, has yet to be fully assessed.

while the decay of the information contained on mitchondria would seem to decay with age, offspring do not encounter the same problem. clearly the mitchondria found in the egg are 'out of the box' new.

some consideration for the fact that while our dna is constantly being blended, the info contained on the mitochondria is rather ancient, and has not changed. the link between cancer-massive rate of uncontrolled reproduction, and the function of the organelle to produce energy, which fuels the reproduction is compelling.

would be curious to see if there is a link between population of mitchondria and some forms of cancer.
-dwindling mc, kicking out a massive increase in energy, or the mc, itself, massively replicating before it expires.

mark l. said at January 5, 2012 11:39 AM:

as for the specific role of mitchondria in aging...

wondering if there is a stronger correlation between aging of the mother and her offspring, than the paternal influence.

it would be difficult to filter out a multitude of x-factors(poorly designed organs being the first consideration), but if there is a relation, it should be evident, ever so minutely, between maternal aging and life expectancy of offspring, relative to the paternal aging.

willis said at January 5, 2012 1:57 PM:

This will never do. If we cure senility, who will ever vote democrat?

Gary said at January 5, 2012 10:59 PM:

See: Gene Therapy , (15 September 2011) | doi:10.1038/gt.2011.134

Mitochondrial gene replacement in human pluripotent stem cell-derived neural progenitors

S Iyer, E Xiao, K Alsayegh, N Eroshenko, M J Riggs, J P Bennett and R R Rao

Abstract
Human pluripotent stem cell-derived neural progenitor (hNP) cells are an excellent resource for understanding early neural development and neurodegenerative disorders. Given that many neurodegenerative disorders can be correlated with defects in the mitochondrial genome, optimal utilization of hNP cells requires an ability to manipulate and monitor changes in the mitochondria. Here, we describe a novel approach that uses recombinant human mitochondrial transcription factor A (rhTFAM) protein to transfect and express a pathogenic mitochondrial genome (mtDNA) carrying the G11778A mutation associated with Leber's hereditary optic neuropathy (LHON) disease, into dideoxycytidine (ddC)-treated hNPs. Treatment with ddC reduced endogenous mtDNA and gene expression, without loss of hNP phenotypic markers. Entry of G11778A mtDNA complexed with the rhTFAM was observed in mitochondria of ddC-hNPs. Expression of the pathogenic RNA was confirmed by restriction enzyme analysis of the SfaN1-digested cDNA. On the basis of the expression of neuron-specific class III beta-tubulin, neuronal differentiation occurred. Our results show for the first time that pathogenic mtDNA can be introduced and expressed into hNPs without loss of phenotype or neuronal differentiation potential. This mitochondrial gene replacement technology allows for creation of in vitro stem cell-based models useful for understanding neuronal development and treatment of neurodegenerative disorders.

and

Development of Mitochondrial Gene Replacement Therapy

Shaharyar M. Khan and James P. Bennett
From the issue entitled "Mitochondria and Neuroprotection—In Memory of Albert L. Lehninger"

Many classic mitochondrial diseases have been described that arise from single homoplasmic mutations in mitochondrial DNA (mtDNA). These diseases typically affect nonmitotic tissues (brain, retina, muscle), present with variable phenotypes, can appear sporadically, and are untreatable. Evolving evidence implicates mtDNA abnormalities in diseases such as Alzheimer''s, Parkinson''s, and type II diabetes, but specific causal mutations for these conditions remain to be defined. Understanding the mtDNA genotype–phenotype relationships and developing specific treatment for mtDNA-based diseases is hampered by inability to manipulate the mitochondrial genome. We present a novel protein transduction technology (protofection) that allows insertion and expression of the human mitochondrial genome into mitochondria of living cells. With protofection, the mitochondrial genotype can be altered, or exogenous genes can be introduced to be expressed and either retained in mitochondria or be directed to other organelles. Protofection also delivers mtDNA in vivo, opening the way to rational development of mitochondrial gene replacement therapy of mtDNA-based diseases.

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