Aging and Retroviruses

  

BY DEREK LOWE

There are a lot of weird things about the human genome, and one of them is the amount of it that seems to be detritus from old viruses. I mentioned this as part of this post in 2021 - the idea is that ancient retroviruses have (over millions of years) taken the occasional opportunity to insert viral DNA sequences into the human germline, which is interesting in itself because we don’t know of any current retroviruses that do that in humans. We are still carrying this stuff around, and by that I mean carrying between five and ten per cent of our entire genomes. A lot of it has deteriorated with time, accumulating mutations of various kinds, but some of these things can still be translated into RNA, and some of those can still be transcribed into proteins. And since we know that both proteins and RNA species can have numerous activities in the cell, and we also know that functional genes can emerge from previously nonfunctional RNA sequences. . .well, it makes these things worth keeping an eye on.

It’s already known that these endogenous retrovirus sequences have influenced the evolution of the human immune system and can be involved in some forms of cancer as well. in this new paper, that list grows to include aging in general. That builds on recent work showing that another form of viral debris, LINE1 sequences (which were mentioned in the 2021 blog post linked above), seem to be involved in cellular senescence. There were reports about ten years ago that these genetic elements became more actives in senescent cells, and that’s starting to look prescient. The new culprit described here is HERV-K, which is probably the most recently integrated retrovirus in humans, and (surely not by coincidence) one of the most transcriptionally active as well.

The paper shows that HERVK envelope proteins (and their associated mRNAs) are detectable at greater and greater levels as cells age, and that this relationship holds in rodents and primates (by cell, tissue, and serum assays), and even in tissue and serum from aged human donors. They even say that they are able to detect entire retrovirus-like-particles (RVLPs) in the cytoplasm of aged cells. The claim is that increased expression of these things actually helps drive cellular senescence, and this is demonstrated in two directions. Deliberately increasing the expression of these proteins does seem to lead to senescence in cell culture (as compared to controls), and exposing cells to extracellular levels of them does as well. This effect could be reversed by treatment with an anti-HERVK-envelope-protein antibody.

These retroviral proteins set off a constant immune response, which ties in with the general observation that nonstop inflammation is a characteristic of aging in many tissues. The paper extends the connection in vivo by looking at a similar mouse retrovirus (MMRV). It’s found to be expressed at greater levels in degenerating joint tissues, and this phenotype could be alleviated by siRNA knockdown. Taken together, the proposal is that retroviral proteins (HERVK envelope in particular, and likely others?) are being reactivated as cells age, that this is directly responsible for some parts of the aging phenotype, and that this presents an opportunity for therapeutic intervention.

A lot of this story has not been filled out yet, but this very much looks like it’s worth investigating. It would be particularly interesting to see what happens when you target these proteins in aged rodents or primates, perhaps through antibody treatment or through genetic modifications as a proof-of-concept. You’d also want to try treating them before they show signs of aging to see how that progresses. My own guess - and that’s all it is - is that this is all still secondary to aging itself (i.e., I don’t think we get old just because of retroviruses). But it’s certainly possible that the underlying aging phenotype is being exacerbated, perhaps greatly, by this route, and that we could alleviate things by targeting it. Let’s find out!

https://www.science.org/content/blog-post/aging-and-retroviruses

Town Hall Ventures’ Andy Slavitt on 'how to invest in Medicaid and health tech'

 Part of Andy Slavitt’s core mission at Town Hall Ventures is proving that health tech companies can make a viable business out of reaching low-income people who also face social challenges, like a lack of housing or nutritious food options. It’s a bold assertion that hasn’t been proven out yet, though a handful of Town Hall Ventures’ portfolio companies — including Unite Us and Alphabet spinout Cityblock  — have already achieved valuations over $1 billion.

The stakes are growing steadily higher, especially for the millions who signed up for Medicaid coverage during the public health emergency and who risk losing it as temporary expansions end. And by investing in teams they trust to embed in vulnerable communities, build culturally sensitive products, and develop sophisticated analytics to assess social needs, Slavitt and his team are hoping to set an example for other venture funds who have historically avoided Medicaid.

“The clinical answers are not so hard. I can’t emphasize that enough,” Slavitt said. Though the diagnoses affecting low-income patients are largely the same as the ones affecting those with commercial insurance, the health care system isn’t set up to accommodate homeless people, or medically complex pediatric patients in health care deserts, he said. 

“What’s different largely speaking is that being poor really sucks and being miles away from anyone who can really care for you really sucks and needing to fill out 10 forms to get housing or child care or any of these other things is a big deterrent to getting care,” he said. “A system that doesn’t welcome you, doesn’t recognize where you live, really doesn’t work.” 

From an investment perspective, he said, there’s potential for a “decent margin — not a huge margin” in helping the country’s roughly 90 million Medicaid patients get better preventive health care, avoiding more expensive treatment in the future. “There’s no bigger market than Medicaid,” he said. 

STAT spoke with Slavitt in San Francisco, where he and other investors and health care executives descended earlier this month for the J.P. Morgan Health Care Conference. This conversation has been edited for length and clarity. 

What types of companies do you think are best equipped to solve these problems?

The good news is there’s an awakening that the most needed area of investment is also investable space. Not everyone has figured it out.

There’s two types of ways of thinking about investing. One starts with how do I find a market opportunity and make a lot of money? And the other starts with is there a really big problem that I can figure out how to solve? Not every problem in health care will be solved with innovation. But some can, and the ones that can are the ones where you’ve got a clinical, social, behavioral model that addresses the need of a specific population where there’s also some payment model that allows you to meet those needs.

If you look across Medicaid, you can follow the journey from moms to babies, pregnant moms to pediatrics, complex pediatrics, then school-based programs, justice and teen mental health programs, disability, all the way up to [dual Medicare and Medicaid eligibles and eldercare]. We have activities in all those buckets. We have investments in most of those buckets. 

Finding people who really understand these problems at a really operational finite level [is important]. Take a company like Cityblock Health. There are several thousand available housing units in New York that don’t get used for homeless people because they’re only available for people with a psych diagnosis. And in order to get a psych diagnosis, you’ve got to go find a psychiatrist in New York, then make it to the appointment, then it gets rejected. … They’ve got a team of psychiatrists that do that, nothing but that, and they get people into housing. 

How will you know you’ve been successful?

If we’re massively successful, [Town Hall] will invest a few billion dollars over our life into these communities. We need hundreds of billions of dollars invested, and there’s all this capital that sits there trapped [in the health care industry] … or is repatriated to shareholders because these are incredibly profitable companies. And they come into these communities and they take the profits out. Money needs to be reinvested back into these communities. 

Do the communities you’re focused on use technology any differently than wealthier ones?

SMS is less expensive to use than a browser. There are subtleties. I went out to the field with a Cityblock community health partner and I said, “What’s your favorite part of your job?” And she said, “My iPad.” I don’t hear that a lot in health care, but she said, “I bring this into someone’s apartment and I can build access to the whole world for them. I can connect them to the thing they need, I can order something for them on the spot and they can see action. I can communicate with their daughter who is a big user of technology.” 

Amazon has a lot to teach us in coming into health care because they know how to deploy technology in ways that don’t feel like technology. 

How are the metrics you use to evaluate companies different from other markets?

It’s imperfect and it’s a little bit of a moving target. We started in earnest on it probably a year ago. We got more resources on our team to be able to collect the information from our companies. It was always part of the process but if you’d asked me the question for each one how are they doing, I wouldn’t have been able to give you a great answer. 

One easy tell, when I talk to a company, is, “Tell me what it is.” Plume, which is a trans health company, they’re like, “we have to reduce anxiety and depression scores very fast.” So they measure that like crazy. If I look at Eleanor Health, which is focused on addiction and recovery treatment, what they basically want to get to is lower craving levels. They don’t measure urine tests [as much] … they’ve learned that the frequency of touch points with people at various stages of their addiction recovery is really important, so they’ll measure that.

There’s a set of consistent metrics, but you’ve got to respect them to tell their own story. At some level they’re going to know their business better. 

If I don’t hear that they’re measuring Net Promoter Score rabidly in the right way, it tells me, OK there’s some other way you’re getting paid than doing your job. 

There’s questions we ask every company like diversity on your management team, diversity on your board, diversity at each level, diversity of promotions. There’s usually other investors at the table, and I’m pretty sure they’re going to ask the question about “how’s your sales acquisition doing?” But my first questions will always be what I think is important. You have to hire diversity, particularly in the early stages, and then their networks will come in. But you have to force it. 

This story, part of a series on health tech for underserved populations, was supported by USC Annenberg Center for Health Journalism’s national fellowship.

https://www.statnews.com/2023/01/31/town-hall-ventures-medicaid-slavitt-health-tech/

US return-to-office rate rises above 50% for first time since pandemic began

 Workers in the U.S. are spending more time in the office again, with occupancy rates surpassing 50% for the first time since the start of the Covid-19 pandemic.

Average office use last week was 50.4% of early 2020 levels in 10 major U.S. cities, according to Kastle Systems, which tracks security swipes into buildings every business day. It is the first time office occupancy has topped 50%, according to Kastle, since March 2020, when Covid-19 forced most workplaces to temporarily shut down.

All 10 of the major cities it tracks surpassed 40% for the first time, Kastle said. 

Workers are still staying home ahead of the weekend, however. Offices are emptiest on Friday, according to Kastle, and they are the most crowded on Tuesdays. In New York, for example, occupancy rates dropped to 26.5% on Friday from 59.8% on Tuesday. 

Companies have been pushing workers to head to the office more, offering hybrid schedules or trying to lure them in with free snacks and other amenities. Some employers, impatient with empty desks, are asking employees to work full-time in an office. City officials are also eager to see workers in business districts, spending money at restaurants or coffee shops. 

On Wednesday, the U.S. House of Representatives was set to vote on a Republican bill to force federal agencies to roll back their telework policies to where they stood as of December 2019 and provide information on how the shift to working from home has affected worker productivity and federal costs. Republican lawmakers say the changes have hurt workers’ ability to do their jobs and created backlogs, while unions and some workers have defended flexibility as key to recruitment and retention.

Separately, Washington, D.C., Mayor Muriel Bowser, a Democrat, has asked the Biden administration to force more federal workers back to the office, hoping for help in reversing a downtown slump that she says has led to closed shops and depressed property values. In a recent speech, Ms. Bowser said the federal government represented one-quarter of the city’s prepandemic jobs and owns or leases a third of its office space. 

"We need decisive action by the White House to either get most federal workers back to the office most of the time or to realign their vast property holdings" for other uses, she said.

The Office of Management and Budget has declined to provide a statistic on how office usage currently compares with prepandemic levels, instead citing a report from the Office of Personnel Management that states 47% of all federal employees nationwide participated in telework in fiscal 2021.

According to Kastle, San Jose, Calif., had the lowest return-to-office rate last week, at 41.1%—though it increased 3 percentage points from the week before. The city is home to many tech companies. 

Two cities in Texas—Austin and Houston—had the highest return-to-office rates at above 60%. 

https://www.foxbusiness.com/economy/us-return-office-rate-rises-above-50-first-time-since-pandemic-began

GoodRx leaked sensitive health information to Facebook and Google, FTC alleges

 The Federal Trade Commission on Wednesday accused GoodRx, the prescription drug discount platform, of sharing sensitive personal information about its users’ prescriptions and health conditions with big tech companies.

GoodRx, which also runs a marketplace for telehealth services, agreed to pay a $1.5 million civil penalty for sharing users’ health data — like medication use or health conditions — with third parties including Facebook, Google, and Twilio for advertising. The settlement marks the first time the FTC has taken action under its Health Breach Notification Rule, and comes as the federal government looks to crack down on consumer companies deceptively selling and sharing health data.

GoodRx collects sensitive information from users and from pharmacy benefit managers who confirm when a customer buys a drug using a discount from GoodRx. About 55 million people have used GoodRx since 2017.

The FTC said GoodRx shared that data with Facebook to target its own customers with medication-specific ads on Facebook and Instagram, among other breaches. In 2019, the company gathered a list of users who bought specific medications like blood pressure or heart disease drugs, and shared email addresses, phone numbers, and mobile advertising IDs with Facebook so their profiles could be tagged for health-related advertisements, FTC said. Sharing sensitive health data with advertisers directly contradicts its own privacy policy, according to the FTC.

Regulators also said GoodRx let third parties it shares data with tap its user health information for other purposes, including to improve their own advertising and to conduct research and development.

Under the Health Breach Notification Rule, the FTC can penalize companies for exposing potentially individually identifiable health information without notifying the people affected.

“Digital health companies and mobile apps should not cash in on consumers’ extremely sensitive and personally identifiable health information,” Samuel Levine, director of the FTC’s Bureau of Consumer Protection, said in a statement. “The FTC is serving notice that it will use all of its legal authority to protect American consumers’ sensitive data from misuse and illegal exploitation.”

GoodRx said in a blog post it did not agree with the allegations and admitted no wrongdoing, but that the settlement would let the company “avoid the time and expense of protracted litigation.”

It also said the issues mentioned in FTC’s complaint had been “ proactively addressed almost three years ago, before the FTC inquiry began,” including by removing a Javascript tracking pixel for sharing data with Facebook. 

https://www.statnews.com/2023/02/01/goodrx-ftc-health-data-leak/

Align Tech beats views

 Q4 total revenues of $901.5 million and 2022 total revenues of $3.7 billion

Board of Directors has authorized a new $1 billion stock repurchase program, to succeed the current $1 billion program that is expected to be completed in Q2 2023

• 2022 total revenues of $3.7 billion, Clear Aligner revenues of $3.1 billion and Systems and Services revenues of $662.1 million

• 2022 revenues were unfavorably impacted by foreign exchange of approximately $193.8 million(1) compared to 2021

• 2022 operating margin of 17.2%, non-GAAP operating margin of 21.5%, and diluted net income per share of $4.61, non-GAAP diluted net income per share of $7.76(3)

• 2022 operating margin was unfavorably impacted by foreign exchange of approximately 2.8 points compared to 2021(1)

• Repurchased $475 million of common stock in 2022(2) with plans to repurchase $250 million more starting in Q1 2023 and expect to entirely complete our 2021 $1 Billion Stock Repurchase Program in Q2 2023

• Q4 total revenues of $901.5 million, and diluted net income per share of $0.54, non-GAAP diluted net income per share of $1.73(3)

• Q4 revenues were unfavorably impacted by foreign exchange of approximately $16.0 million sequentially and approximately $67.6 million year over year(1)

https://finance.yahoo.com/news/align-technology-announces-fourth-quarter-214100161.html

Durbin, bipartisan senators slam FDA’s ‘repeated failures’ at vaping regulation

 A bipartisan group of senators on Wednesday slammed the “repeated failures” at the Food and Drug Administration (FDA) to regulate e-cigarettes and take action against companies illegally marketing products to minors.

Led by Sen. Dick Durbin (D-Ill.), the lawmakers sent a letter to Health and Human Services Secretary Xavier Becerra urging him to “do everything in your power to right the ship and take meaningful action to fix FDA’s persistent leadership failures and prevent youth from a lifetime of nicotine addiction.”

The FDA is currently 16 months past a court-ordered deadline to finish reviewing e-cigarette applications, and the lawmakers criticized the agency for saying it needs another six months to complete its work for the e-cigarettes with the largest market share. An estimated 1 million children may now be at risk of picking up vaping before the FDA finishes its review, Durbin said. 

Durbin has been a leading Senate advocate against youth vaping and has repeatedly called for federal regulators to do a better job protecting children by immediately removing e-cigarettes and vaping products from store shelves.  

“For nearly a decade, the agency has neglected its duty under the law to regulate e-cigarettes, jeopardizing the health of millions of children. Now, after yet another delay in FDA’s efforts to regulate the e-cigarette marketplace, it is now clear to us that FDA is adrift and lives are at risk,” the lawmakers wrote.

The U.S. District Court for the District of Maryland ordered the FDA to finish reviewing e-cigarette applications by Sept. 9, 2021. But the agency has only completed reviews of about half of those e-cigarettes, the lawmakers said.

“Some of the most popular e-cigarettes used by children today do not have market authorization but are on store shelves only because the FDA has granted a free pass and decided to exercise enforcement discretion,” they wrote.

The FDA was given the authority to regulate the marketing, manufacturing and distribution of tobacco products in 2009 when Congress passed the Tobacco Control Act. 

But an independent report from the Reagan-Udall Foundation released in December found the FDA’s “failure to take timely enforcement action jeopardizes public health and undermines credibility and effectiveness in tobacco product regulation.”

The report faulted the FDA’s inconsistent approach to regulation for being at least partially to blame for the popularity of vaping among young people.

Instead of proactively creating regulations, the report found the agency’s tobacco center has been “forced to operate primarily in a reactive mode, moving from one challenge to the next.”

Brian King, the head of the FDA’s tobacco division, published an update on Tuesday saying the center would respond to the Reagan-Udall report later this month.

https://thehill.com/policy/healthcare/3839881-durbin-bipartisan-senators-slam-fdas-repeated-failures-at-vaping-regulation/

White House won’t say if Biden classified documents searches are over

 The White House on Wednesday refused to say if there will be more searches for classified documents kept at private properties belonging to President Biden following the FBI search of his Rehoboth Beach, Del., home earlier in the day in which every room was looked at.

Ian Sams, a White House spokesperson for investigations, told reporters he is “going to be really careful not to characterize what the Justice Department is doing in their investigation” when asked if he can confidently say whether he thinks there are more classified documents in Biden’s possession.

Federal investigators conducted a search of the Rehoboth home from 8:30 a.m. until noon on Wednesday. Biden’s attorney said later that investigators found no classified materials on the property.  

“The Justice Department is engaged in an ongoing investigation, an ongoing investigation, I should add, that the president has been fully cooperative in offering unprecedented access to his home in Wilmington, to his home — every single room of his home in Rehoboth as well as the one in Wilmington and giving them access to the information they need,” Sams said.

“He’s moving quickly to get them the information that they need,” he added.

When asked if the FBI has conducted searches of any other locations associated with the president, Sams said he would not “want to speak too much to the DOJ [Department of Justice] practices and an ongoing investigation.” 

The Sams remarks appeared a bit more cautious than comments weeks ago from White House press secretary Karine Jean-Pierre, who described a search of Biden’s Wilmington, Del., home as “complete” before investigators found more materials at that residence.

Sams also said he would not “get ahead of potential speculation” of future steps taken in the probe when asked if the president would be willing to sit for an interview as part of the investigation. 

Biden earlier Wednesday did not respond to questions by reporters about whether he would sit with the special counsel appointed to oversee the matter.

The White House has been adamant that Biden has cooperated in the investigation into materials found from his time as vice president and as a senator at his home and a former office he once used in Washington, D.C.  

Multiple outlets reported Tuesday that the FBI had also searched Biden’s old Washington, D.C., office he used from 2017 to 2019 after a small number of classified documents were found there in November.

https://thehill.com/homenews/administration/3839837-white-house-wont-say-if-biden-classified-documents-searches-are-over/