2012 July 29 Sunday
Immune Dendritic Cells Accumulate Harmful Proteins

Our immune cells accumulate damaged proteins that impair their function. We need to replace these cells every few decades and keep our immune systems rocking.

"Aging is known to affect immune function, a phenomenon known as immunosenescence, but how this happens is not clear," said study leader Laura Santambrogio, M.D., Ph.D. , associate professor of pathology and of microbiology & immunology at Einstein. "Our study has uncovered several ways in which aging can worsen the body's overall ability to mount an effective immune response.

What I want: cell therapies that will replace senescent immune cells with youthful and highly functioning immune cells. Such therapies will not only reduce sickness and death from infection. The immune system also manages to kill some cancer cells. So one of the reasons that cancer incidence rises with age is immune system aging that undermines the ability of immune cells to identify and attack cancer cells. In fact, some cancers get held in a dormant state by the immune system. Plus, a healthy youthful immune system probably removes toxic beta amyloid protein from the brain and thereby prevents Alzheimer's disease. So your immune system's vigor matters even more than most people imagine.

These researchers found that old immune dendritic cells contain lots of damaged proteins.

The current study is the first to examine whether age-related oxidative stress compromises the function of a type of immune cell called dendritic cells. "Dendritic cells are known as the 'sentinels of the immune system' and alert the rest of the immune system to the presence of microbial invaders," explained Dr. Santambrogio. "When you are exposed to viruses or bacteria, these cells engulf the pathogens and present them to the immune system, saying in effect, 'There's an infection going on, and here is the culprit—go get it.'"

Dr. Santambrogio, in collaboration with Einstein colleagues Fernando Macian-Juan, M.D., Ph.D. , and Ana Maria Cuervo, M.D., Ph.D. , isolated dendritic cells from aging mice and found that oxidation-damaged proteins had accumulated in those cells and had caused harmful effects. For example, oxidatively modified proteins hampered the function of endosomes, the cell's organelle where pathogens are inactivated.

One of the proposed Strategies for Engineered Negligible Senescence (SENS) is to remove accumulated intracellular junk. Likely we would benefit if we could remove the damaged proteins that accumulate in dendritic cells as we age. However, just outright replacing the old dendritic cells with young dendritic cells would deliver greater benefit as old cells have DNA damage that puts them at risk of becoming cancers too.

Possibly antioxidants could boost dendritic cell function so that vaccines would work better in old folks. But that remains to be proven. Also, the antioxidants would be very unlikely to restore youthful function.

When the mice were injected with a potent antioxidant in the abdominal cavity daily for two weeks, some of the effects of oxidative stress were reversed. This finding has implications for designing vaccines or therapies for humans, especially the elderly, whose weakened immune systems increase their susceptibility to infections and cancer, and reduces vaccine effectiveness. "Many elderly people respond very poorly to vaccination, so perhaps a cycle of therapy with antioxidants before vaccination might improve their immune response to vaccines," Dr. Santambrogio noted.

If I could choose a single system in the body for full rejuvenation I would choose the immune system, especially for anti-cancer protection. In second place I'd probably put the vascular system for lower risk of strokes and better nutrient delivery to the brain. After that I'd opt for either the brain (a faster brain combined with many years of accumulated skills) or muscles (heart muscle especially).

By Randall Parker    2012 July 29 10:18 PM   Entry Permalink | Comments (6)
2010 July 07 Wednesday
Short Telomeres Markers For Higher Cancer Risk

The telomere caps on chromosomes shorten as you age. A prospective study finds shorter telomeres are linked to a higher risk of cancer.

Peter Willeit, M.D., of Innsbruck Medical University, Innsbruck, Austria, and colleagues conducted a study to assess the association between leukocyte telomere length and risk of both new-onset cancer and cancer death. Leukocyte telomere length was measured by quantitative polymerase chain reaction (laboratory technique used to analyze DNA) in 787 participants, free of cancer in 1995, and part of the prospective, population-based Bruneck Study in Italy. The primary outcomes analyzed included the incidence of new cancer and cancer mortality over a follow-up period of 10 years (1995-2005).

During follow-up, a total of 92 of 787 participants (11.7 percent) developed cancer. Analysis indicated that short telomere length at the beginning of the study was associated with new cancer independently of standard cancer risk factors. Compared with participants in the longest telomere length group, participants in the middle length group had about twice the risk of cancer, and those in the shortest length group had approximately three times the risk. Cancer incidence rates were inversely related to telomere length, with participants in the group with the shortest telomere length having the highest rate of cancer.

The obvious question: what's the direction of causality? I am guessing that short telomeres are not causing cancer. One possibility: cells that have shorter telomeres have lived tougher lives (metaphorically speaking) and are more damaged than cells in same age people who have longer telomeres. While that's probably true of the cells of the body as a whole I suspect another mechanism is at work with leukocytes. More on this below

It would be interesting to know whether short telomeres in leukocytes is well correlated with short telomeres in other cell types, especially in the cell types listed here as having become cancerous.

Short telomere length was also associated with a higher rate of death from cancer. "Of note, telomere length was preferentially associated with individual cancers characterized by a high fatality rate such as gastric, lung, and ovarian cancer, but less so with tumors linked to better prognosis," the authors write. They add that telomere length had a similar predictive value for cancer in both men and women and in various age groups.

So what's the other mechanism of causation I suspect? Leukocytes are white blood cells. In other words, immune cells. White blood cells do not just kill invading cells. The immune system also (sometimes) goes after cancer. Leukocytes with short telomeres are less able to divide and therefore are less able to mount an attack against cancer cells. It could be that short telomeres matter because they indicate an aged immune system that won't fight cancer.

Dr. Zheng Cui of Wake Forest University has found that some special mice and rare people have extreme anti-cancer immune systems. He has also found that the anti-cancer capability of immune systems decline with age. That decline in anti-cancer capability is due in part to immune cells losing the ability to divide due to worn down telomeres.

What we need to slash our risks of cancer: Rejuvenated immune systems.

By Randall Parker    2010 July 07 09:23 PM   Entry Permalink | Comments (2)
2010 March 07 Sunday
Vitamin D Needed For Immune T Cell Activation

Another reason to make sure you get enough vitamin D: the ability to respond to infections. Vitamin D plays a key role in activating killer T cells after those cells detect a viral or bacterial pathogen.

Scientists at the University of Copenhagen have discovered that Vitamin D is crucial to activating our immune defenses and that without sufficient intake of the vitamin, the killer cells of the immune system – T cells - will not be able to react to and fight off serious infections in the body.

For T cells to detect and kill foreign pathogens such as clumps of bacteria or viruses, the cells must first be 'triggered' into action and 'transform' from inactive and harmless immune cells into killer cells that are primed to seek out and destroy all traces of a foreign pathogen.

The researchers found that the T cells rely on vitamin D in order to activate and they would remain dormant, 'naïve' to the possibility of threat if vitamin D is lacking in the blood.

It is worth noting in this context that influenza primarily spreads in the winter when people are getting less sun exposure and therefore less vitamin D synthesis in their skin. So during winter low vitamin D level might be contributing to the spread of flu virus due to lower immune function.

By Randall Parker    2010 March 07 09:02 PM   Entry Permalink | Comments (5)
2010 January 27 Wednesday
Macrophage Growth Factor Rejuvenates Immune System?

Seems to work for mice at least.

By comparing the immune responses of both, young and old mice, to bacterial infection they found that the number of macrophages, one of the major cell populations involved in the elimination of infecting bacteria, decreases rapidly in aged mice. This decline in the number of fighters and the associated weakness of the immune defense may be responsible for the age-associated increase in susceptibility to infections. The HZI researchers have succeeded to enhance the resistance to an infection in aged mice by treating them with a macrophage-specific growth factor. This treatment increases the amount of macrophages in aged mice and improves their capacity to fight the infection. This study has been published in the current issue of the scientific magazine "Journal of Pathology".

The main task of the immune system is to protect the body against invading pathogens. For this purpose, a variety of different cell types and molecular factors work together in a complex network. Together, they compose a highly effective defense front line. As we are getting older, our immune system changes: infections are more frequent and more severe, some immune cell types lose certain properties and their functionality declines – in short: the immune system grows old. "Since the immune system protects our body against infections, to keep the immune system young and functional is a crucial factor for a healthy aging," says Eva Medina, head of the HZI research group "Infection Immunology".

While many elderly people die from infections there's more riding on immune system rejuvenation than just infection fighting. There's a bell-shaped distribution between people in immune system ability to attack cancer and the ability of the immune system to fight cancer declines with age. Immune system rejuvenation might cause a large decline in the incidence of diagnosed cancer as youthful immune systems will some day probably kill off many cancers at early stages of development.

By Randall Parker    2010 January 27 12:36 AM   Entry Permalink | Comments (1)
2008 July 06 Sunday
Immune System Rejuvenation Needed For TB Treatment

Aged immune systems hobble the ability of old people to fight off tuberculosis (TB). These aged immune systems also explain higher rates of death of old people from the flu and other infectious diseases.

COLUMBUS, Ohio – Manipulating the immune system in elderly people appears to be the most likely way to help older patients wage an effective battle against tuberculosis, a new study suggests.

Mathematical modeling of how mice respond to TB infection suggests that potential therapy options for elderly TB patients could either increase their white blood cell count or enhance infected cells’ interaction with their immune system.

This report illustrates how scientists trying to treat specific diseases end up running into the need to rejuvenate parts of the body. In this case what is needed is immune system rejuvenation.

Simulations of TB infection in an old mouse showed that increasing the number of infection-fighting white blood cells, called CD4 T cells, could be particularly effective at bolstering the mouse’s immune response, which naturally slows with aging. Older humans have similar delays in their immune response, meaning that they have a much more difficult time controlling TB than do younger people with an active infection.

The math modeling also suggested that making changes to macrophages, cells that essentially eat infecting bacteria, could enhance those cells’ interactions with other warriors in the immune system, reducing the concentration of bacteria in the lungs associated with TB infection.

As we age senescent immune cells end up displacing active immune cells and we need techniques for killing off the senescent cells. Imagine a machine that is analogous to a kidney dialysis machine that is specialized at separating senescent T cells from blood. If these old cells could simply be removed from the body the remaining T cells that retain the ability to divide could fill in the space made available by the removal of the senescent immune cells. Or perhaps a gene therapy could instruct senescent cells to commit cell suicide (apoptosis).

A rejuvenated immune system might itself kill off other senescent cell types. So methods to rejuvenate the immune system will provide many rejuvenation benefits. Plus, r, a younger immune system would probably reduce the incidence of cancer.

By Randall Parker    2008 July 06 10:19 PM   Entry Permalink | Comments (3)
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