It happens to everyone. With age come discomforts: achy joints, wounds that heal more slowly, and a rising risk for cancers, heart disease, dementia, arthritis, and other illnesses. Those changes follow an uptick in inflammatory molecules over the course of a lifetime, according to a large and growing body of research. The link between age, inflammation, and disease is so well established, it has a name: inflammaging.

Now, researchers are unraveling the details of how the inflammatory process changes over the lifespan, what instigates the shift, and how it might be possible to interfere with the process. The work suggests interventions ranging from new drugs to new motivations for healthy habits like exercise that can slow the aging process, says Ron DePinho, a cancer biology and aging researcher at the University of Texas MD Anderson Cancer Center in Houston.

Research on inflammaging also illustrates the nuanced challenge of taking the reins of inflammation to sustain health later in life. Although many people fixate on the need to reduce inflammation, it is more important to sustain the appropriate amount of it as a means toward extending quality rather than quantity of life, says Judith Campisi, a cell biologist at the Buck Institute for Research on Aging, an independent research facility in Novato, Calif.

“What happens with age is you lose control of inflammation,” she says. “Even if you’re five years old, you will never heal a wound without an initial inflammatory response. It’s not always bad. It’s sometimes good.”

Hallmarks of aging

As people age, according to numerous studies, increasing amounts of pro-inflammatory cytokines and other inflammation-related molecules circulate in the blood alongside a rise in localized inflammation. When the shift occurs depends on the person, DePinho says, but 50 is generally when inflammation starts to increase, with a dramatic shift after 60.

That uptick tracks closely with disease trends. Beginning in the early sixties, risks rise substantially for the most common chronic diseases of aging: cancer, diabetes, heart disease and dementia, DePinho says. Starting at 65, the number of people with Alzheimer’s doubles every five years. In the U.S., 80 percent of adults over 65 have at least one chronic condition. By age 85, a third of people may have Alzheimer’s, while a third of men and one-fourth of women have had cancer. People with more inflammation in their bodies have a higher risk of disease.

Scientists have identified a dozen biological changes that correspond with age. All of those hallmarks of aging are associated with inflammation, and inflammation is considered a pillar of aging, says Luigi Ferrucci, a geriatrician and epidemiologist at the Intramural Research Program of the NIH’s National Institute on Aging in Baltimore, Maryland.

For example, as people get older, their immune cells lose their protective functions and stop doing the job of fighting off invaders, turning into what scientists call senescent cells. Other kinds of cells can also become senescent in response to stress. They cease replicating, no longer do their jobs, and start to secrete powerful inflammatory molecules that cause yet more cells to become senescent in a self-perpetuating cycle.

A relentless loop

Meanwhile, DNA damage inside cells accumulates over time, especially at the tips of chromosomes in protective regions called telomeres, which are long stretches of bunched-up DNA. Each time a cell divides, its telomeres become shorter until they reach a critical length that is perceived by the cell as DNA damage or instability, which may induce cellular senescence.

As telomeres become damaged, they initiate a signaling process through proteins that turn certain genes on and off. Some of the genes affected support the function of mitochondria (the cell components that produce energy). As a result of the gene disruption, mitochondria become defective and leak their DNA into cells, sparking inflammation.

Scientists used to consider telomere shortening, mitochondrial damage, inflammation, and other processes as separate theories of aging that could contribute to diseases like cancer, DePinho says. Now it is clear that all of these changes are connected and that inflammation acts like a “co-conspirator” in the aging process.

As chronic inflammation sets in, it becomes harder for the immune system to perform routine tasks, like detecting and eliminating cancer cells and pathogens, which could make people more likely to develop diseases. Inflammation in the body may also activate immune cells in the brain called microglia, according to one theory, causing inflammation, weakening the blood-brain barrier, and destroying nerve cells, ultimately contributing to the development of Alzheimer’s.

This burgeoning understanding of inflammaging as a relentless circuit of steps that all exacerbate inflammation is revealing new ways to break the cycle.

Aging better

Efforts to develop anti-aging interventions that target inflammation are challenging because they need to be specific to avoid causing more harm than good, Ferrucci says. Trying to tackle the chronic inflammation of aging with general anti-inflammatory drugs, for example, could make people more susceptible to disease by impairing the inflammation that our bodies need for staying healthy. “When you have an infection, if you don’t have inflammation, you’re going to die,” Ferrucci says. “Shutting down inflammation with a bomb like a corticosteroid or some monoclonal antibodies works. It’s also quite dangerous.”

One of the most promising new strategies for dealing with inflammaging is attacking senescent cells, experts say. In mice, a low-dose combination of two drugs, called Dasatinib and Quercetin, appears to be particularly effective at getting rid of these deadbeat cells and reducing inflammation in the intestines with the potential to extend lives. Clinical trials are now underway with these and other so-called senolytics to see if the same kinds of compounds might kill senescent cells and break the cycle of inflammation and disease in people too, says DePinho.

Other ongoing approaches include efforts to identify drugs that could restore telomeres, enhance mitochondrial function, and activate anti-aging genes, a strategy DePinho is working on. Some over-the-counter supplements claim to boost levels of proteins called sirtuins, which help cells respond to stresses, and a molecule called NAD+, which helps mitochondria function, among other roles, and dwindles in half from youth to middle age. Although evidence has been seriously questioned and these products have been over-hyped, DePinho says, further study may illuminate new anti-aging properties of sirtuins.

Scientists are hopeful that they are getting closer to understanding which interventions will help most, and studies in mice illustrate the tantalizing possibilities. “Tissues retain a remarkable capacity to renew themselves if you remove the underlying instigators of the aging process,” DePinho says.

Advances in immunology are lending new insights into how we can allow good inflammation to proceed while squashing the bad that can come from too much of it, Ferrucci adds. “As we discover the nuances of inflammation,” he says, “then it may be possible to find drugs that do not shut down inflammation completely.”

Age-fighting behaviors

For now, there are simple steps people can take to address inflammaging in their own bodies, experts say, including exercise. Regular physical activity enhances DNA repair, improves mitochondrial function, activates sirtuins, and, studies show, can reduce the risk of cancer, diabetes, heart disease, and Alzheimer’s. Regular vigorous activity is best, but as little as 15 minutes a day can make a difference, DePinho says, and even leisure activities help.

Dietary choices, too, can improve the chronic inflammatory state of inflammaging, according to a variety of studies that support eating a Mediterranean-style diet with an emphasis on whole grains, produce, nuts, and fish. Eating a wide variety of vegetables may also help sustain the gut microbiome, which tends to become less resilient and contribute to rising levels of inflammation with age. Each Saturday, when Ferrucci goes to the market to shop for the week, he buys 10 different kinds of vegetables, based on this emerging evidence. “That is something that has been suggested in the literature,” he says. “And I think that’s a simple way of following that advice.”

Body fat releases cytokines that promote inflammation, DePinho adds, so using exercise and diet to control weight can have extra benefits. He also advises people to avoid or quit smoking, a habit known to increase DNA damage and drive inflammation. Finding ways to relax is another useful goal, as chronic stress has been linked to shortened telomeres, accelerated aging, and inflammatory diseases. Adequate sleep and meditation can help reduce stress, DePinho says.

Healthy habits like these are important throughout life, Ferrucci says, but they become especially important as the mechanisms that protect our cells from damage become less functional with age. That accumulating damage is a key source of inflammation. “Intervening in any possible way becomes more important as you become older,” he says.

Leukemia frequently originates from the so-called leukemic stem cell, which resides in a tumor promoting and protecting niche within the bone marrow. Scientists from the Max Planck Institute of Biochemistry in Martinsried, Germany, have found a new way to make these cells vulnerable by specifically dislodging these cells from their niches.

Since blood cells have a limited lifespan, are lost during bleeding or are used up during infections, they must be replaced continuously. This supply is ensured by the so-called hematopoietic stem cells in the bone marrow. These cells can develop into any type of blood cell.

In chronic myeloid leukemia, the hematopoietic stem cell undergoes a genetic mutation by recombining chromosome 9 and 22. As a result, gene building blocks fuse that would otherwise not be in contact with each other. The incorrectly assembled chromosome is called Philadelphia chromosome and harbors the construction manual for the so-called BCR-ABL oncogene. This causes the leukemic stem cell to behave selfishly and divide at the expense of healthy blood stem cells.

Without Kindlin-3 no leukemia

A leukemic stem cell creates an environment termed the malignant niche that ensure its survival and proliferation. To remain in this tumor-promoting niche, the leukemic stem cell uses so-called integrins to attach itself to a scaffold of extracellular proteins, the so-called extracellular matrix, and to neighboring cells. In the leukemic stem cell, the activity and function of the integrins is facilitated by an intracellular protein called Kindlin.

Peter Krenn, first author of the study, explains: “The isoform Kindlin-3 is only used by blood cells. If mice harbor leukemic stem cells that lack Kindlin-3, they do not develop leukemia. Without Kindlin-3 and active integrins, the leukemic stem cells cannot attach themselves to their niche environment and are released from the bone marrow into the blood. Since they cannot home elsewhere either, they remain in the blood. There the leukemic stem cells lack the urgently needed support, which they usually receive from the niche, and die.”

New therapeutic approach: Kindlin-3 and CTLA-4

The new finding that the leukemic stem cells express a protein called CTLA-4 on their surface, which is absent from healthy blood stem cells, allowed the researchers to distinguish a leukemic blood stem cell from a healthy blood stem cell. The scientists used the CTLA-4 receptor as a shuttle to deliver a Kindlin-3 destroying compound, into leukemic stem cells. Peter Krenn explains: “CTLA-4 is only briefly present on the cell surface and is then rapidly recycled back into the cell and then back to the cell surface again. This enabled us to introduce a Kindlin-3 degrading siRNA into the cell by coupling it to a CTLA-4-binding RNA sequence, which is called aptamer. The leukemic stem cell without Kindlin-3 is flushed from the bone marrow and the leukemia loses its origin and runs out of fuel.”

Peter Krenn summarizes: “In our current study we have developed a new therapeutic approach to treat chronic myeloid leukemia in mice. However, the principle of the therapy is universally valid. The inhibited Kindlin-3 production and consequent loss of integrin function prevents the cancer cells from being able to adhere and settle in tumor-promoting niches. I assume that this method will also prevent the cancer cells of other types of leukemia from settling and that these diseases could thus become much more treatable.”

Max-Planck-Gesellschaft. (2020, October 23). New therapeutic approach against leukemia. ScienceDaily. Retrieved November 16, 2020 from resource link.

One proposed cause of aging is the accumulation of epigenetic noise – or disruptions in gene expression patterns – that lead to decreased tissue function and reduced regenerative abilities. In a recent study, researchers from the Harvard Medical School (HMS) addressed the epigenetics-based theory of aging which postulates that changes in the epigenome cause cellular malfunctions and age-related diseases over time.

Their research continues to explore whether DNA methylation drives cellular change and whether restoring functionality in living organisms is possible. Results report restored vision in mice achieved by restoring aged cells in the retina to their youthful function and a reversal of vision loss in mice with a condition mimicking human glaucoma.

Epigenetic reprogramming in mice

The proof-of-concept study represents the first successful attempt at reversing the biological clock in animals via epigenetic reprogramming. To prove this, the team of researchers examined the potential of reversing the age of cells by controlling DNA methylation.

Led by Yuancheng Lu, research fellow at Harvard Medical School, the study’s authors examined whether the regenerative capacity of young animals can be replicated in adult mice by delivering a modified three-gene combination via an adeno-associated virus (AAV) into the retinal ganglion cells of adult mice with optic nerve injury. They targeted cells within the central nervous system as it is the first part of the body affected by aging.

“Having previously found evidence for epigenetic noise as an underlying cause of aging, we wondered whether mammalian cells might retain a faithful copy of epigenetic information from earlier in life that could serve as instructions to reverse aging,”” the research team commented.

Restoring eyesight and rejuvenating cells

Lu and colleagues found that the treatment had multiple beneficial effects on the eye health of mice; it promoted nerve regeneration following optic nerve injury in mice with damaged optic nerves, caused a two-fold increase in the number of surviving retinal ganglion cells after injury, and increased nerve regrowth by five times. These results suggested that the modified gene combination approach was safe and could potentially be used to revolutionize the treatment of ocular degeneration as well as that of other organs affected by aging.

Following their promising findings, Lu and his team partnered with colleagues at Schepens Eye Research Institute of Massachusetts to perform two experiments: one testing whether the three-gene cocktail could restore glaucoma-related vision loss and a second one to test whether this approach could reverse vision loss associated with the regular biological aging process.

The team found that the treatment led to increased nerve cell electrical activity as well as a notable increase in visual acuity, which was measured by the animals’ ability to see moving vertical lines across a screen in a model of glaucoma. “To our knowledge, this is the first example of vision-loss reversal after glaucomatous injury has occurred; previous attempts have focused on neuroprotection delivered at an early stage to prevent further disease progression,” the authors wrote.

Similarly, the treatment had beneficial effects on the vision of elderly mice; it was able to restore vision in older mice with diminishing vision caused by normal aging. Following the treatment, the researchers found reversed patterns of DNA methylation which suggest that DNA methylation is an active agent in the aging process.

“These data indicate that mammalian tissues retain a record of youthful epigenetic information—encoded in part by DNA methylation—that can be accessed to improve tissue function and promote regeneration in vivo,” the authors concluded.

Clinical implications

As the first findings that prove the reversal of glaucoma-induced vision loss with no associated negative side effects in the cohort, the latest results will need to be confirmed in further animal work before human trials can be initiated. Nonetheless, the success of the new approach represents a potential breakthrough in regenerative medicine and an array of possible treatment pathways for age-related health conditions.

“Our study demonstrates that it’s possible to safely reverse the age of complex tissues such as the retina and restore its youthful biological function,” said David Sinclair, PhD, co-director of the Paul F. Glenn Center for Biology of Aging Research at HMS, who is senior author of the published paper in Nature. “If affirmed through further studies, these findings could be transformative for the care of age-related vision diseases like glaucoma and to the fields of biology and medical therapeutics for disease at large,” he explained. 

Intravenous injection of bone marrow derived stem cells (MSCs) in patients with spinal cord injuries led to significant improvement in motor functions, researchers from Yale University and Japan report Feb. 18 in the Journal of Clinical Neurology and Neurosurgery.

For more than half of the patients, substantial improvements in key functions — such as ability to walk, or to use their hands — were observed within weeks of stem cell injection, the researchers report. No substantial side effects were reported.

The patients had sustained, non-penetrating spinal cord injuries, in many cases from falls or minor trauma, several weeks prior to implantation of the stem cells. Their symptoms involved loss of motor function and coordination, sensory loss, as well as bowel and bladder dysfunction. The stem cells were prepared from the patients’ own bone marrow, via a culture protocol that took a few weeks in a specialized cell processing center. The cells were injected intravenously in this series, with each patient serving as their own control. Results were not blinded and there were no placebo controls.

Yale scientists Jeffery D. Kocsis, professor of neurology and neuroscience, and Stephen G. Waxman, professor of neurology, neuroscience and pharmacology, were senior authors of the study, which was carried out with investigators at Sapporo Medical University in Japan. Key investigators of the Sapporo team, Osamu Honmou and Masanori Sasaki, both hold adjunct professor positions in neurology at Yale.

Kocsis and Waxman stress that additional studies will be needed to confirm the results of this preliminary, unblinded trial. They also stress that this could take years. Despite the challenges, they remain optimistic.

“Similar results with stem cells in patients with stroke increases our confidence that this approach may be clinically useful,” noted Kocsis. “This clinical study is the culmination of extensive preclinical laboratory work using MSCs between Yale and Sapporo colleagues over many years.”

“The idea that we may be able to restore function after injury to the brain and spinal cord using the patient’s own stem cells has intrigued us for years,” Waxman said. “Now we have a hint, in humans, that it may be possible.”

Yale University. (2021, Feb

ruary 22). Scientists repair injured spinal cord using patients’ own stem cells. ScienceDaily. Retrieved May 16, 2021 from  

NAD+ (Nicotinamide Adenine Dinucleotide) is an essential coenzyme found in all living cells. It is used in mitochondrial function to convert nutrients to ATP, which gives energy to all cells, regulates DNA repair, and lengthens telomeres.  While enhancing Healthy cells, NAD may also cause Senescent cells (Zombie Cells) to increase SASP production.  This causes unwanted side effects like chills.

Most clinics do not take this extra step which enhances full body homeostasis by removing the burden of excess senescent cells.

Also allowing a faster more efficient uptake of NAD without the unwanted side effects.

Benefits of Our proprietary NAD+ IV and Senolytics program.

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Reduces inflammation as well, a synergystic effect combined with the anti- inflammatory properties of Senolytics

Exposure to toxic environments, chemicals, pollution, and diseases causes inflammation. Chronic inflammation will damage our cells and DNA. NAD+ stimulates enzymes, which prevent and reverse cellular and DNA damage.

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