Friday, August 10, 2018

Some Thoughts on Aging – Denial versus Acceptance versus Rejoicing

Those of you who have read some of my past articles are aware that I wrote mostly about various aspects of primary care and our dysfunctional healthcare delivery system overall. A few years ago I wrote a post for KevinMD on moving to a retirement community. Since then I became interested in the actual process of aging and did some further posts for KevinMD. Why do we age? Why do our various organs lose function over time when does it start and how fast does it occur? Can we do anything about it; can we slow it down? Why do complex chronic illnesses become more prevalent with aging? Can we prevent those? What research is ongoing? And from there - would a pill delay aging? What are the efforts to actually reverse aging, a search for the Fountain of Youth? After a few years of research came “Longevity Decoded – The 7 Keys To Healthy Aging” which was published in April, 2018 and is available on Amazon. This article and those to follow are based on this journey of exploration.           Your comments will be most welcome.

We are all aging every day but mostly we ignore it, do not recognize it or deny it. Then all of a sudden we look in the mirror and realize that older age has found us. Even then each person deals with aging differently.

There is a parody by an unknown author of Dr Seuss’ “The Cat in the Hat” which takes a negative perspective on aging. Perhaps “The Cat in the Hat” says much of what many people feel and think.
But there are other perspectives, many much more positive.

After I told a friend about the concept of what I was writing, he sent me the following: “About 25 years ago I received a video about the Adirondack Park. When the park was established - in the late 1800's I believe - the New York state government drew a blue line around the immense region. Individuals living inside the park were allowed to stay, and pass their land onto heirs, but they could not sell their property to others. Over the succeeding generations the land not passed on to heirs became owned by the state. The video was about a gentleman in his 60's who was one of the last of his generation and focused on preserving what had been the Adirondack way of life - realizing it was about to fade into history. In the video as he talked he slowly unfolded a 6' wooden ruler. He went on to indicate that the 72 inches represented the average lifespan in years for many folks. He then indicated his age on the ruler and made the point that while he hoped to live beyond the end of the ruler he realized his time was short and he had limited time to accomplish his goals.

“My dad had recently passed away - at the age of 72 - and in his tools I found a folding ruler. After seeing the video I picked up the ruler and unfolding it became aware I was beyond the half way point. Over the years I have often opened and looked at the ruler. I recall at 50 feeling that time was speeding up. For some reason now that I'm in my 60's the passage of time bothers me less - but I am aware of the limited amount left. I am also focusing more on what happens when, hopefully, I go beyond the end of the ruler.

“It seemed to me your audience may benefit from an increased awareness of time and what they can do to productively live their lives now with that goal of having an enjoyable existence in the future.”

Good advice. Here are some other bits of personal philosophy about aging and its impact on us as individuals.

Ian Brown in his book The Experiment rebels at aging through his diary that he starts at age sixty. As recounted by Gerard Helferich in a Wall Street Journal book review, “His journal is largely a protest against decline. His hearing is fading, along with his memory. His knees ache. His arches have fallen. His face sags, and a patch of hair over his forehead resembles ‘a random stand of corn that somehow got planted away from the main field.’ He has rosacea, age spots and a hemorrhoid. Though he and his friends still hike and ski, it’s a case of ‘ever-older men doing daring things, to prove we’re still daring, and therefore not older.’ Mostly Ian Brown regrets not taking more risks… he is afraid that he hasn’t lived up to his promise… A friend reminds him that we spend the first half of our lives wishing we looked like someone else and the second half wishing we looked like our former selves.”
Willard Spiegelman, on the other hand, in his early 70’s when he wrote Senior Moments may be, says  Helferich, “closer to the end than Mr. Brown, [but] he doesn’t betray dread or regret but a gentle, teasing acceptance. ‘We come into the world alone, with a cry…we exit alone, to confront the final eternal silence. The fun, all the pleasure and adventure, lies in between.’ [The two books] striking dissimilarities—in content and form but especially in attitude and voice—derive from the authors’ varying views on life more than from their relative ages or their divergent attitudes about the end of life. Whether we are 60 or 70, or 80 or 90, how fiercely we rage against the coming of that good night depends above all on how we have embraced the sum of our days.”

“The Cat in the Hat” has a clearly negative perspective on advanced years and certainly not all would agree. My friend with the 72-inch ruler is rather philosophical while recognizing that time is indeed moving on.  Brown wants to deny and so does “daring” adventures while Spiegelman is more accepting of what lies ahead.

The perspective of an older person is related mostly to how he or she perceives life and how he or she has lived their earlier years. It is with that background of life and living that we come to terms – or not - with growing older.

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Cancer ‘Vaccine’ Eliminates Tumors In Mice

Activating T cells in tumors eliminated even distant metastases in mice, Stanford researchers found. Lymphoma patients are being recruited to test the technique in a clinical trial.

Ronald Levy (left) and Idit Sagiv-Barfi led the work on a possible cancer treatment that involves injecting two immune-stimulating agents directly into solid tumors.
Steve Fisch

Injecting minute amounts of two immune-stimulating agents directly into solid tumors in mice can eliminate all traces of cancer in the animals, including distant, untreated metastases, according to a study by researchers at the Stanford University School of Medicine.

The approach works for many different types of cancers, including those that arise spontaneously, the study found.

The researchers believe the local application of very small amounts of the agents could serve as a rapid and relatively inexpensive cancer therapy that is unlikely to cause the adverse side effects often seen with bodywide immune stimulation.

“When we use these two agents together, we see the elimination of tumors all over the body,” said Ronald Levy, MD, professor of oncology. “This approach bypasses the need to identify tumor-specific immune targets and doesn’t require wholesale activation of the immune system or customization of a patient’s immune cells.”

One agent is already approved for use in humans; the other has been tested for human use in several unrelated clinical trials. A clinical trial was launched in January to test the effect of the treatment in patients with lymphoma. (Information about the trial is available online.)

Levy, who holds the Robert K. and Helen K. Summy Professorship in the School of Medicine, is the senior author of the study, which was published Jan. 31 in Science Translational Medicine. Instructor of medicine Idit Sagiv-Barfi, PhD, is the lead author.
‘Amazing, bodywide effects’

Levy is a pioneer in the field of cancer immunotherapy, in which researchers try to harness the immune system to combat cancer. Research in his laboratory led to the development of rituximab, one of the first monoclonal antibodies approved for use as an anti-cancer treatment in humans.

Some immunotherapy approaches rely on stimulating the immune system throughout the body. Others target naturally occurring checkpoints that limit the anti-cancer activity of immune cells. Still others, like the CAR T-cell therapy recently approved to treat some types of leukemia and lymphomas, require a patient’s immune cells to be removed from the body and genetically engineered to attack the tumor cells. Many of these approaches have been successful, but they each have downsides — from difficult-to-handle side effects to high-cost and lengthy preparation or treatment times.

“All of these immunotherapy advances are changing medical practice,” Levy said. “Our approach uses a one-time application of very small amounts of two agents to stimulate the immune cells only within the tumor itself. In the mice, we saw amazing, bodywide effects, including the elimination of tumors all over the animal.”

Cancers often exist in a strange kind of limbo with regard to the immune system. Immune cells like T cells recognize the abnormal proteins often present on cancer cells and infiltrate to attack the tumor. However, as the tumor grows, it often devises ways to suppress the activity of the T cells.

Levy’s method works to reactivate the cancer-specific T cells by injecting microgram amounts of two agents directly into the tumor site. (A microgram is one-millionth of a gram). One, a short stretch of DNA called a CpG oligonucleotide, works with other nearby immune cells to amplify the expression of an activating receptor called OX40 on the surface of the T cells. The other, an antibody that binds to OX40, activates the T cells to lead the charge against the cancer cells. Because the two agents are injected directly into the tumor, only T cells that have infiltrated it are activated. In effect, these T cells are “prescreened” by the body to recognize only cancer-specific proteins.
Cancer-destroying rangers

Some of these tumor-specific, activated T cells then leave the original tumor to find and destroy other identical tumors throughout the body.

The approach worked startlingly well in laboratory mice with transplanted mouse lymphoma tumors in two sites on their bodies. Injecting one tumor site with the two agents caused the regression not just of the treated tumor, but also of the second, untreated tumor. In this way, 87 of 90 mice were cured of the cancer. Although the cancer recurred in three of the mice, the tumors again regressed after a second treatment. The researchers saw similar results in mice bearing breast, colon and melanoma tumors.

    I don’t think there’s a limit to the type of tumor we could potentially treat, as long as it has been infiltrated by the immune system.

Mice genetically engineered to spontaneously develop breast cancers in all 10 of their mammary pads also responded to the treatment. Treating the first tumor that arose often prevented the occurrence of future tumors and significantly increased the animals’ life span, the researchers found.

Finally, Sagiv-Barfi explored the specificity of the T cells by transplanting two types of tumors into the mice. She transplanted the same lymphoma cancer cells in two locations, and she transplanted a colon cancer cell line in a third location. Treatment of one of the lymphoma sites caused the regression of both lymphoma tumors but did not affect the growth of the colon cancer cells.

“This is a very targeted approach,” Levy said. “Only the tumor that shares the protein targets displayed by the treated site is affected. We’re attacking specific targets without having to identify exactly what proteins the T cells are recognizing.”

The current clinical trial is expected to recruit about 15 patients with low-grade lymphoma. If successful, Levy believes the treatment could be useful for many tumor types. He envisions a future in which clinicians inject the two agents into solid tumors in humans prior to surgical removal of the cancer as a way to prevent recurrence due to unidentified metastases or lingering cancer cells, or even to head off the development of future tumors that arise due to genetic mutations like BRCA1 and 2.

“I don’t think there’s a limit to the type of tumor we could potentially treat, as long as it has been infiltrated by the immune system,” Levy said.

The work is an example of Stanford Medicine’s focus on precision health, the goal of which is to anticipate and prevent disease in the healthy and precisely diagnose and treat disease in the ill.

The study’s other Stanford co-authors are senior research assistant and lab manager Debra Czerwinski; professor of medicine Shoshana Levy, PhD; postdoctoral scholar Israt Alam, PhD; graduate student Aaron Mayer; and professor of radiology Sanjiv Gambhir, MD, PhD.

Levy is a member of the Stanford Cancer Institute and Stanford Bio-X.

Gambhir is the founder and equity holder in CellSight Inc., which develops and translates multimodality strategies to image cell trafficking and transplantation.

The research was supported by the National Institutes of Health (grant CA188005), the Leukemia and Lymphoma Society, the Boaz and Varda Dotan Foundation and the Phil N. Allen Foundation.

Stanford’s Department of Medicine also supported the work.

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