Skip to main content

aging

A New Piece of the Alzheimer’s Puzzle

Posted on by

A couple enjoying a hot drink

Credit: National Institute on Aging, NIH

For the past few decades, researchers have been busy uncovering genetic variants associated with an increased risk of Alzheimer’s disease (AD) [1]. But there’s still a lot to learn about the many biological mechanisms that underlie this devastating neurological condition that affects as many as 5 million Americans [2].

As an example, an NIH-funded research team recently found that AD susceptibility may hinge not only upon which gene variants are present in a person’s DNA, but also how RNA messages encoded by the affected genes are altered to produce proteins [3]. After studying brain tissue from more than 450 deceased older people, the researchers found that samples from those with AD contained many more unusual RNA messages than those without AD.


An Aspirin a Day for Older People Doesn’t Prolong Healthy Lifespan

Posted on by

Hands holding a pill and a glass of water

Credit: iStock/thodonal

Many older people who’ve survived a heart attack or stroke take low-dose aspirin every day to help prevent further cardiovascular problems [1]. There is compelling evidence that this works. But should perfectly healthy older folks follow suit?

Most of us would have guessed “yes”—but the answer appears to be “no” when you consider the latest scientific evidence.  Recently, a large, international study of older people without a history of cardiovascular disease found that those who took a low-dose aspirin daily over more than 4 years weren’t any healthier than those who didn’t. What’s more, there were some unexpected indications that low-dose aspirin might even boost the risk of death.


Unlocking the Brain’s Memory Retrieval System

Posted on by

Memory Trace in Mouse Hippocampus

Credit:Sahay Lab, Massachusetts General Hospital, Boston

Play the first few bars of any widely known piece of music, be it The Star-Spangled Banner, Beethoven’s Fifth, or The Rolling Stones’ (I Can’t Get No) Satisfaction, and you’ll find that many folks can’t resist filling in the rest of the melody. That’s because the human brain thrives on completing familiar patterns. But, as we grow older, our pattern completion skills often become more error prone.

This image shows some of the neural wiring that controls pattern completion in the mammalian brain. Specifically, you’re looking at a cross-section of a mouse hippocampus that’s packed with dentate granule neurons and their signal-transmitting arms, called axons, (light green). Note how the axons’ short, finger-like projections, called filopodia (bright green), are interacting with a neuron (red) to form a “memory trace” network. Functioning much like an online search engine, memory traces use bits of incoming information, like the first few notes of a song, to locate and pull up more detailed information, like the complete song, from the brain’s repository of memories in the cerebral cortex.


Lens Crafting

Posted on by

Credit: Salma Muhammad Al Saai, Salil Lachke, University of Delaware, Newark

Live long enough, and there’s a good chance that you will develop a cataract, a clouding of the eye’s lens that impairs vision. Currently, U.S. eye surgeons perform about 3 million operations a year to swap out those clouded lenses with clear, artificial ones [1]. But wouldn’t it be great if we could develop non-surgical ways of preventing, slowing, or even reversing the growth of cataracts?  This image, from the lab of NIH-grantee Salil Lachke at the University of Delaware, Newark, is part of an effort to do just that.

Here you can see the process of lens development at work in a tissue cross-section from an adult mouse. In mice, as in people, a single layer of stem-like epithelial cells (far left, blue/green) gives rise to specialized lens cells (middle, blue/green) throughout life. The new cells initially resemble their progenitor cells, displaying nuclei (blue) and the cytoskeletal protein actin (green). But soon these cells will produce vast amounts of water-soluble proteins, called crystallins, to enhance their transparency, while gradually degrading their nuclei to eliminate light-scattering bulk. What remains are fully differentiated, enucleated, non-replicating lens fiber cells (right, green), which refract light onto the retina at the back of the eye.


Cryo-EM Images Capture Key Enzyme Tied to Cancer, Aging

Posted on by

Each time your cells divide, telomeres—complexes of specialized DNA sequences, RNA, and protein that protect the tips of your chromosomes—shorten just a bit.  And, as the video shows, that shortening renders the genomic information on your chromosomes more vulnerable to changes that can drive cancer and other diseases of aging.

Consequently, over the last few decades, much research has focused on efforts to understand telomerase, a naturally occurring enzyme that helps to replace the bits of telomere lost during cell division. But there’s been a major hitch: until recently, scientists hadn’t been able to determine telomerase’s molecular structure in detail—a key step in figuring out exactly how the enzyme works. Now, thanks to better purification methods and an exciting technology called cryo-electron microscopy (cryo-EM), NIH-funded researchers and their colleagues have risen to the challenge to produce the most detailed view yet of human telomerase in its active form [1].

This structural biology advance is a critical step toward learning more about the role of telomerase in cancers, as well as genetic conditions linked to telomerase deficiencies. It’s also an important milestone in the quest for drugs targeting telomerase in different ways, perhaps to slow the growth of cancerous cells or to boost the proliferative capacity of life-giving adult stem cells.

One reason telomerase has been so difficult to study in humans is that the enzyme isn’t produced at detectable levels in the vast majority of our cells. To get around this problem, the team led by Eva Nogales and Kathleen Collins at the University of California, Berkeley, first coaxed human cells in the lab to produce larger quantities of active telomerase. They then used fluorescent microscopy, along with extensive knowledge of the enzyme’s biochemistry, to develop a multi-step purification process that yielded relatively homogenous samples of active telomerase.

The new study is also yet another remarkable example of how cryo-EM microscopy has opened up new realms of scientific possibility. That’s because, in comparison to other methods, cryo-EM enables researchers to solve complex macromolecular structures even when only tiny amounts of material are available. It can also produce detailed images of molecules, like telomerase, that are extremely flexible and hard to keep still while taking a picture of their structure.

As described in Nature, the researchers used cryo-EM to capture the structure of human telomerase in unprecedented detail. Their images reveal two lobes, held together by a flexible RNA tether. One of those lobes contains the highly specialized core enzyme. It uses an internal RNA template as a guide to make the repetitive, telomeric DNA that’s added at the tips of chromosomes. The second lobe, consisting of a complex of RNA and RNA-binding proteins, plays important roles in keeping the complex stable and properly in place.

This new, more-detailed view helps to explain how mutations in particular genes may lead to telomerase-related health conditions, including bone marrow failure, as well as certain forms of anemia and pulmonary fibrosis. For example, it reveals that a genetic defect known to cause bone marrow failure affects an essential protein in a spot that’s especially critical for telomerase’s proper conformation and function.

This advance will also be a big help for designing therapies that encourage telomerase activity. For example, it could help to boost the success of bone marrow transplants by rejuvenating adult stem cells. It might also be possible to reinforce the immune systems of people with HIV infections. While telomerase-targeted treatments surely won’t stop people from growing old, new insights into this important enzyme will help to understand aging better, including why some people appear to age faster than others.

As remarkable as these new images are, the researchers aren’t yet satisfied. They’ll continue to refine them down to the minutest structural details. They say they’d also like to use cryo-EM to understand better how the complex attaches to chromosomes to extend telomeres. Each new advance in the level of atomic detail will not only make for amazing new videos, it will help to advance understanding of human biology in health, aging, and disease.

References:

[1] Cryo-EM structure of substrate-bound human telomerase holoenzyme. Nguyen THD, Tam J, Wu RA, Greber BJ, Toso D, Nogales E, Collins K. Nature. 2018 April 25. [Epub ahead of publication]

Links:

High Resolution Electron Microscopy (National Cancer Institute/NIH)

Nogales Lab (University of California, Berkeley)

Collins Lab (University of California, Berkeley)

NIH Support: National Institute of General Medical Sciences   


Next Page