Archive for ‘Aging’

November 7, 2011

Do Bacteria Age? Biologists Discover the Answer Follows Simple Economics

Do bacterial cells get “older” after repeated divisions? What would that even mean, once an original “mother” cell has divided into two “daughters”? Well, there are certain things one might look for as indicators of aging. For example, accumulation of molecular damage and slower rates of division in succeeding generations.

Previous studies have given conflicting results. One one hand it seems that many bacterial cells in later generations do show signs of having aged. But on the other, if aging is measured over the average of the whole population, it isn’t found.

The latest study found that, just as a population genetic model predicted would be optimal, half the daughter cells in a new generation appeared to be young and rejuventated, while the other half had accumulated the signs of aging.

Do Bacteria Age? Biologists Discover the Answer Follows Simple Economics

“Aging in organisms is often caused by the accumulation of non-genetic damage, such as proteins that become oxidized over time,” said Lin Chao, a professor of biology at UC San Diego who headed the study. “So for a single celled organism that has acquired damage that cannot be repaired, which of the two alternatives is better—to split the cellular damage in equal amounts between the two daughters or to give one daughter all of the damage and the other none?”

The UC San Diego biologists’ answer—that bacteria appear to give more of the cellular damage to one daughter, the one that has “aged,” and less to the other, which the biologists term “rejuvenation”—resulted from a computer analysis Chao and colleagues Camilla Rang and Annie Peng conducted on two experimental studies.

Further reading:

Temporal Dynamics of Bacterial Aging and Rejuvenation

November 7, 2011

Erasing the Signs of Aging in Human Cells Is Now a Reality

Human induced pluripotent stem cells (iPSCs) are adult body cells that have been treated in vitro to revert to a pluripotent state very close to embryonic stem cells. They were first produced in 2007, and the process of generating them has become progressively faster and more efficient. The resulting iPSCs now also have fewer defects and are less susceptible to becoming cancerous.

Although iPSCs are not precisely the same as embryonic stem cells, they share the property of lacking all traces of cellular aging, such as shortened telomeres and altered metabolism. In other words, they have been rejuvenated, having full-length telomeres and normal mitochondrial metabolism, gene expression profiles, and levels of oxidative stress.

Like other pluripotent cells, iPSCs can in principle differentiate into any type of body cell. Progress is being made in figuring out the exact recipe needed to actually produce cells that are equivalent to any adult cell type – some types are easier to make than others.

Given adult cells, of any particular type, derived from iPSCs, the natural question is whether such cells are also free of traces of aging that existed in the original adult cells from which the iPSCs were derived. The answer is that they are rejuvenated in comparison to the cells they were originally derived from – even if those original cells came from human centenarians, and (surprisingly) even if the original cells had entered the senescent stage in which they could no longer divide.

Of course, all this work was accomplished in vitro. There’s no obvious way to apply it to the whole body of an older person, or even to a complex organ. Perhaps such cells can eventually be used as a therapy for patients with Parkinson’s disease or to grow replacement arteries or tracheas. But that kind of development is still somewhere in the future.

Erasing the Signs of Aging in Human Cells Is Now a Reality

[S]enescent cells, programmed into functional iPSC cells, re-acquired the characteristics of embryonic pluripotent stem cells.

In particular, they recovered their capacity for self-renewal and their former differentiation potential, and do not preserve any traces of previous aging. To check the “rejuvenated” characteristics of these cells, the researchers tested the reverse process. The rejuvenated iPSC cells were again differentiated to adult cells and compared to the original old cells, as well as to those obtained using human embryonic pluripotetent stem cells (hESC).

“Signs of aging were erased and the iPSCs obtained can produce functional cells, of any type, with an increased proliferation capacity and longevity,” explains Jean-Marc Lemaitre who directs the Inserm AVENIR team.

The key to this new development was finding an improved recipe for the transcription factors used to effect reprogramming. In addition to the usual four factors (OCT4, SOX2, c-MYC and KLF4), the researchers included NANOG and LIN28 to erase traces of cell senescence.

Further reading:

Ageing stem cells from centenarian rejuvenated

‘Rejuvenated’ stemcells coaxed from centenarian

Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state

November 4, 2011

Cell-Aging Hack Opens Longevity Research Frontier

This is pretty important, even though it’s only a proof of concept – not even a first step to developing a useful therapy for age-related health afflictions. What’s been done is to show that a state (senescence), which old cells reach when they near the limit of their useful lives, is not just a somewhat benign way of stopping the cell from becoming cancerous. Instead, senescent cells that aren’t eliminated naturally (by the immune system or by apoptosis) and remain in the body can degrade the health of the organism. Further, causing such cells to be eliminated is not only possible, but improves the organism’s overall health even though it does not lengthen lifespan. (And even this much has only been demonstrated in genetically altered mice, not humans.)

Cell-Aging Hack Opens Longevity Research Frontier

Research into longevity, that most fundamental and intractable of all human health challenges, moves slowly. It deserves to be described in terms of years, not individual studies. But once in a rare while, a finding has the potential to be a landmark.

Such is the case with a new experiment that flushed old, broken-down cells from the bodies of mice, slowing their descent into the infirmities of age.

The large caveats that inevitably apply to mouse studies still apply here, in spades. But even with those, the findings mark the first time that cellular senescence — its importance debated by biologists for decades — has been experimentally manipulated in an animal, demonstrating a fantastic new tool for studying its role in human aging.

The research involved a series of experiments, and if you’re up on your molecular biology, the details are interesting.

read more »

October 22, 2011

Worms with Genes for Long Life Pass on Longevity to Offspring…Even Without the Genes

Epigenetic changes in your parents’ chromosomes could affect your lifespan. At least, that is, if you’re a simple roundworm.

Recent research has shown that some epigenetic changes in plant DNA can be inherited. (See here, here). However, these changes aren’t robust, and tend to drop out after a few generations.

The epigenetic changes in plants that were heritable involved DNA methylation. The new research on roundworms (Caenorhabditis elegans) concerned a slightly different type of epigenetic change: methylation of a histone protein. Histones make up chromatin, the scaffolding around which DNA is wrapped around in chromosomes. There are four different histones, and two copies of each of these form a nucleosome. About 146 base pairs of DNA are wrapped around each nucleosome. The expression of genes whose DNA is wrapped around a nucleosome can be affected by the methylation state of the H3 histone.

Previous research had found that decreased levels of methylation of a specific part of the H3 histone resulted in longevity extensions of C. elegans by up to 30%. More specifically, a protein complex called H3K4me3 does the job of methylating the critical location in the H3 histone. Mutations of certain components of H3K4me3 were known to bring about the longevity extension effect.

How Longevity Is Passed On

Anne Brunet, an associate professor of genetics at the Stanford School of Medicine, found that mutations in a chromatin-modifying complex also significantly increased lifespan in C. elegans. The complex, known as the histone H3 lysine 4 trimethylation (H3K4me3) complex, is responsible for methylating a chromatin packaging protein called histone H3. This methylation is often associated with the increased expression of genes in the vicinity.

When Brunet and her colleagues knocked down members of the H3K4me3 complex—such as the WDR-5 and SET-2—they extended C. elegans life by up to 30 percent, suggesting that the epigenetic changes regulated by the complex controlled genes related to lifespan.

“Basically we think that the reason why those worms live longer is because they have less of this H3K4 mark at specific loci in the genome,” Brunet explained. “That probably results in changes in the expression of some genes,” such as those that regulate the aging process, she added.

That much was understood before the latest research. The new and rather surprising thing the new research has shown is that even if the mutations affecting H3K4me3 levels are eliminated in succeeding generations, the longevity extending effect persists for two more generations. The research found that expression of certain genes affecting metabolism – which often in turn affects longevity – persisted across generations, suggesting that other, as yet unknown, epigenetic changes occurred due to the original changes in H3 methylation.

The research paper itself concludes:

Our observations are consistent with the notion that H3K4me3 at specific loci may not be completely erased and replenished. Alternatively, the ASH-2/WDR-5/SET-2 complex could control the expression of the genes responsible for the erasure and replenishment of histone methylation marks between generations. Modulation of H3K4me3 modifiers in parents may also affect an unidentified protein or RNA that could in turn be inherited and cause lifespan changes.

Further reading:

Long life passed down through generations

Live long, pass it on

Worms with Genes for Long Life Pass on Longevity to Offspring…Even Without the Genes

Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans

September 21, 2011

Scientists Turn Back the Clock on Adult Stem Cells Aging

The main function of adult stem cells is to enable the replacement of old or damaged cells of most types, from neurons to skin to the liver. One of the main reasons that organisms as a whole suffer from aging is that their adult stem cells do too, almost like any other cell type.

An important differences between stem cells and other types of cells is that there is a limit to how often an ordinary cell can divide (to create new cells of the same type). This limit is controlled by telomeres – structures on the ends of chromosomes that are gradually shortened every time a cell divides, in part because DNA copying mechanisms cannot accurately copy the ends of DNA strands. In stem cells, however, a mechanism is active that can rebuild shortened telomeres. (This also happens in cancer cells, unfortunately.)

However, in spite of telomere repair in stem cells, they still experience aging, so there must be more to aging than telomeres. One factor is the accumulation of DNA damage due to the inherent imperfections in DNA repair mechanisms.

The research in question here compared young adult stem cells with cells of the same type that had been allowed to divide repeatedly in cultures, in order to determine what changed. One important difference found was the accumulation of DNA segments called Alu element retrotransposons. This type of noncoding DNA is common in primate genomes. However, the accumulation that occurs in aging stem cells appears to be toxic to the cells and eventually forces them into a senescent state.

The good news is that when copying of these Alu elements is suppressed, stem cells are able to regain their self-renewing properties. Naturally, this is being investigated further for possible applications in slowing the overall aging process.

Scientists Turn Back the Clock on Adult Stem Cells Aging

The regenerative power of tissues and organs declines as we age. The modern day stem cell hypothesis of aging suggests that living organisms are as old as are its tissue specific or adult stem cells. Therefore, an understanding of the molecules and processes that enable human adult stem cells to initiate self-renewal and to divide, proliferate and then differentiate in order to rejuvenate damaged tissue might be the key to regenerative medicine and an eventual cure for many age-related diseases. A research group led by the Buck Institute for Research on Aging in collaboration with the Georgia Institute of Technology, conducted the study that pinpoints what is going wrong with the biological clock underlying the limited division of human adult stem cells as they age.

“We demonstrated that we were able to reverse the process of aging for human adult stem cells by intervening with the activity of non-protein coding RNAs originated from genomic regions once dismissed as non-functional ‘genomic junk’,” said Victoria Lunyak, associate professor at the Buck Institute for Research on Aging.

Further reading:

Inhibition of activated pericentromeric SINE/Alu repeat transcription in senescent human adult stem cells reinstates self-renewal