Daily Archives: March 2, 2022

Aging is a particularly troublesome affair, and until recently it was considered to be an inescapable fact of life. Over the past few decades, however, scientists have discovered that aging follows a predictable path. Unsurprisingly, there is great interest in avoiding that path.

As we age, we experience a gradual decline of physiological function. Over time, our cells accumulate damage and their performance suffers. When the damage reaches a threshold, cells die. Fortunately, there is a system for replacing the dying cells stem cells. Unfortunately, stem cells also age. Consequently, their performance suffers, and they lose their capacity to create healthy new cells.

The new biotechnology firm Altos Labs has recently announced it was taking on aging. At first glance, it is hard to get excited about this. After all, a half-dozen biotech firms have made similar statements over the past decade or so. Altos Labs, which has already secured $3 billion in funding, hasnt released much information about their strategy, only that they are focused on cellular rejuvenation programming to restore cell health and resilience, with the goal of reversing disease to transform medicine. Catchy sales pitch, but not a lot of substance.

Altos Labs has, however, released a lot of information about the scientists theyve recruited, and it is an impressive list, comprising some of the superstars in aging-related disorder research. These scientists backgrounds would suggest Altos Labs has a two-pronged research strategy: 1) reverse the damage that occurs as we age and 2) rejuvenate stem cells capacity to create healthy new cells. A spa day and a cocktail, basically.

Stress ages us. Thus, one of the keys to living a long and healthy life is to relax. We cant escape stress, but if we relax after a stressful event, we can escape many of the consequences of stress.

Stress also ages our cells. Admittedly, they arent dealing with psychological stress from poverty or global pandemics, but they have their own problems, such as nutrient deprivation and viral infection. These cellular stressors can damage a cells proteins, and if there is a lot of damaged protein, a cell cant function well. Cells cannot escape stress. They may not become infected, but they will suffer some form of stress eventually. Luckily, cells have a mechanism for escaping the consequences of stress: the integrated stress-response (ISR) pathway.

When cellular stressors are detected, the ISR initiates spa mode. However, instead of relaxing while a masseuse rubs away muscle knots, cellular spa mode involves shutting down non-essential cellular operations and cleansing the cell of damaged proteins. If the cleansing is successful, the cell is rejuvenated. If not, then ISR presses the termination button. The cell dies, but ideally, a stem cell quickly creates a healthy new cell to replace it.

ISR is more active as we get older, which means cells spend more time in spa mode. A comparison of adult and older male mice demonstrated an increase of ISR activity levels in all tested tissues, including kidney, liver, colon, brain, testes, pancreas, lung, and heart.

However, it is not clear if the increase in ISR activity is a good thing. On one hand, it might promote health in old animals by rejuvenating cells. On the other hand, it might instead contribute to destroying cells unnecessarily.

Destroying a damaged cell can be a good thing, as long as it is quickly replaced with a healthy new cell. However, adult stem cells appear to age with the person. As stem cells age, their ability to create healthy new cells deteriorates. Consequently, a cell might die because ISR has determined it was too damaged, only to be replaced with a cell that is almost equally as damaged.

Essentially, this is like terminating an overstressed employee whose performance has dropped. Then, you wait six months to hire a new employee who is slightly less stressed. A couple months later, you lay off the new employee. During that six-month period, other employees will have to shoulder extra responsibility. Their stress will grow, their performance will drop, and next thing you know, youve laid off the whole department. Catastrophic organ failure is the main cause of age-related disorders.

It is tempting to speculate that inhibiting ISR in adults could solve a lot of problems. Sure, thered be no more spa day, but thered also be no more mass layoffs. But its not that simple. ISR inhibition does enhance memory and lifespan. However, ISR activation reduces the severity of Huntingtons disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis. Thus, the ISR appears to play a beneficial and detrimental role in health depending on the context. Altos Labs scientists will have to gain a better understanding of ISRs context-dependent effects before they can create new anti-aging therapeutics.

No matter how efficient the body is at rejuvenating cells, cells will die and need to be replaced. As we age, however, replacing cells takes more time. For example, healing of a fractured bone takes much longer in older individuals than in younger individuals.

Stem cells are responsible for replacing damaged cells. Like any other cell, stem cells are vulnerable to cellular stressors. This likely contributes to their own aging, but there is also evidence that stem cells DNA changes as during physiological aging. More specifically, the DNAs structure is changed (called an epigenetic change), but not the DNAs sequence. In other words, regardless of their age, stem cells keep the same genes; however, as stem cells age, some genes are tightly packaged up and no longer accessible.

Epigenetic changes are often helpful. For example, a liver-replenishing stem cell will package up all of its neuron genes. When that stem cell creates a new liver cell, the new cell cant accidentally express those neuron genes.

But in the case of aging, the epigenetic changes can be harmful. For example, in addition to packaging the neuron genes, an old liver-replenishing stem cell might package up two other genes:

When a new liver cell is created, it wont be able to access the cleansing gene. As a result, that cell will have a harder time cleansing itself of damaged proteins. Thus, it will die more quickly and need to be replaced again. Unfortunately, that replacement will be slow to arrive because the stem cell cant access the replication gene.

It is unclear why a stem cell would gradually package up helpful and important genes. One hypothesis is that this process ensures we will die. When old organisms die, it frees up resources for young, sexually reproductive organisms. Thus, there is an evolutionary advantage to death.

Regardless of why stem cells do this, it would be helpful to discover a way to liberate some of the genes packaged during aging. Scientists have suspected that this could reverse a stem cells aging-associated functional decline. In 2006, Shinya Yamanaka discovered the tools necessary to do this.

Yamanaka and his team showed that activating four gene regulators (now referred to as the Yamanaka factors) can reset a stem cells epigenetic changes, essentially turning it into a young stem cell. (Yamanaka won the Nobel Prize in Physiology and Medicine for this discovery, and he is a consultant for Altos Labs.)

However, its not as simple as giving a stem cell an endless supply of Yamanaka factor cocktails. When a stem cell is stimulated with all the Yamanaka factors at once, all the genes are unpackaged, resulting in an unspecialized stem cell. This is analogous to resetting your brain to what it was as a baby; your potential would be incredible, but you would need guidance to harness that potential. In the same way, unspecialized stem cells have the potential to become any type of cell, but they will need lots of guidance. And scientists have only begun to scratch the surface on how to guide cells in their development.

However, they might not need to know how to guide development if they want to treat age-related diseases. Researchers recently discovered that moderation is the key to avoiding the problem of unspecialization.

Essentially, stimulating cells with just the right Yamanaka factors at just the right time partially resets the stem cells. These partially reset cells retain their ability to create new cells without extra guidance. Experiments on mice have shown how a partial reset can stop the progression of progeria (a mutation-induced syndrome that mimics rapid aging), can promote the healing of injured muscles, and can protect the liver against medication-mediated damage.

Age-related disorders dementia, arthritis, cancers dont significantly shorten our life span. They are often more cruel than that. Instead, they shorten our health span. They steal our memories, our independence, and our tranquility. From what I can tell, Altos Labs isnt looking for the secret to immortality or even the secret to increasing the human lifespan. They (and all the other anti-aging biotech firms) seem to be searching for a way to make aging less cruel.

So, dont expect an elixir of life that grants immortality anytime soon. Perhaps in a few decades, well know enough about aging to entertain a discussion about extending the human lifespan. But until then, I suspect spas and moderate cocktails are the best path for aging gracefully.

Originally posted here:
Anti-aging isn't a scam, but immortality almost certainly is - Big Think

If your house is on fire, dont wait for the billionaire bucket brigade. The same is true if youre a society facing a pandemic, extreme wealth inequality, an eroding democracy, climate change or a national racial divide.

Each year, the Chronicle of Philanthropy publishes the Philanthropy 50, a list of the biggest donors of the year and an indicator of the giving priorities of Americas ultra-wealthy class. This years feature story is titled, What Pandemic? and summarizes, Despite the continuing Covid threat and racial-justice problems, the nations wealthiest donors have largely returned to old standbys handing out big sums to universities, medicine and their own foundations.

Of the 50 top donors, most gave what could be characterized as legacy gifts: donations to universities and major medical centers that will likely go toward buildings and endowments and are made with an eye toward attaining some sort of edificial immortality.

From these giving priorities, you would never know we were living through a global pandemic, an ecological crisis, spiraling wage and wealth inequality or a national reckoning on racial inequity.

In fact, 14 of the 50 biggest donors gave mainly to their own private foundations or donor-advised funds (DAFs). This includes $15 billion to the Bill and Melinda Gates Foundation and a $1.2 billion donation by William Ackman and Neri Oxfam to their three family foundations.

Donations to a persons own charitable intermediary should not be counted as gifts, since the money is still under their control and hasnt yet gone to an active charity. Forbess list of top donors accounts for this and only includes donations that flow to working charities, not foundations or DAFs.

Wealthy giving preferences have resulted, even during the pandemic, in a warehousing of charity dollars in private foundations and DAFs now estimated to be over $1.1 trillion. This is part of the larger problem of top heavy philanthropy: Over the last few decades, donations from low-and middle-income donors have steadily declined, and almost all growth in charitable giving has come from ultra-wealthy donors.

Wealthy donors love to give to the foundations and DAFs that they control. Roughly 28 percent of charitable donations now go to such intermediaries.

The problem is that a private foundation is only required to give away 5 percent of its assets a year, while overhead, salaries and program expenses can be counted toward this payout rate. And DAFs have no mandated payout at all. These design flaws enable donors to take immediate deductions in the year they transfer funds to their intermediary, while those dollars may sit warehoused for years before flowing to on-the-ground charities.

There have been refreshing exceptions to these trends. MacKenzie Scott, former wife of Jeff BezosJeffrey (Jeff) Preston BezosThe Hill's Morning Report - Russia widens war; Biden speaks tonight Mackenzie Scott donates million to USDA youth programs Elon Musk shuts down Warren claim that he doesn't pay taxes MORE, has aggressively moved to, in her words, empty the vault, distributing over $6 billion during the pandemic directly to grassroots racial justice groups and COVID-19 relief efforts. Similarly, outgoing Twitter CEO Jack Dorsey has aggressively and transparently given billions for COVID-19 relief and poverty alleviation. But they are unfortunately exceptions to the larger trend.

We should be alarmed because, as taxpayers, we subsidize the giving whims of the ultra-wealthy. For every dollar a billionaire donates, we the taxpayer chip in 74 cents of that dollar in lost tax revenue. The wealthier the donor, the bigger their tax subsidy, since these gifts not only reduce their income taxes, but also estate, gift and capital gains taxes. So, there is a legitimate public interest in the scrutinizing the priorities of billionaire donors.

Congress should modernize the rules governing charity to increase the flow of giving to working charities and to discourage the warehousing of billions in donor-controlled intermediaries. Some members have introduced legislation to do this with the Accelerate Charitable Efforts (ACE) Act, but it doesnt go far enough.

Lawmakers should double the payout rate for private foundations to 10 percent and require DAFs to have a payout rate. They should increase the donation tax credit for low- and middle-income donors. And they should establish a lifetime giving cap, so the ultra-wealthy dont get to entirely opt out of paying taxes.

Our society and our vibrant independent nonprofit sector benefit from the generosity of individuals. But we should encourage charitable giving by people of all incomes, not just the wealthy. And we should be vigilant to ensure that philanthropy doesnt become another extension of the power and influence of the billionaire class.

Chuck Collins directs the Charity Reform Project at the Institute for Policy Studies where he coedits Inequality.org. He is author of The Wealth Hoarders: How Billionaires Pay Millions To Hide Trillions.

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Don't wait for billionaire philanthropy to fix America | TheHill - The Hill

People say runners must be running away from something. Death or a bad diet are the most common suggestions, and while there might be something in the bad dietnot that mines bad, exactly, lots of vegetables but also lots of chocolate which I get away with because of the running, though I want the chocolate because of the running so thats a moot point, reallyIm not running because I imagine it brings immortality. I dont want immortality. I dont understand people who want immortality, have they not read The Portrait of Dorian Grey or the story of Tithonus or pretty much anything? Life without death would be as pointless as a story without an ending, and its not as if the planet is so short of people we need a backup supply in the freezer.

I started running for the opposite reason, not to postpone death but to make the most of life. I saw my beloved grandmother pass the last twenty years of her long life in increasing pain and indignity as her bones crumbled and the fear of falling tightened around her. She used to climb mountains. She used to ride bicycles up mountains, back in the 1930s when she was a girl and no-one had told her you need special equipment for that kind of thing. She used to kayak on Scottish lochs, and even later in life, when I remember her, she swam twice a week in the pool at the glamorous hotel where we could help ourselves to big fluffy towels and the water temperature was perfectly bearable even when I first went in.

When I stayed with my grandparents during school holidays we swam together and she took me out for lunch afterwards, prawn sandwiches and cake. But by her early 80s, still with fifteen years to go, she was scared getting in and out of cars in case she lost her balance, because if shed fallen she would have broken bones and her bones didnt mend, and scared of stepping off curbs and though she could probably still have swum and swimming would probably have helped, she couldnt have managed the changing room or climbed into the water. Instead she took to her green velvet chaise longue with a pile of novels and a glass of whiskey, which was all very well in some ways, enviable even, but when you do that it gets harder and harder to do anything else and soon she couldnt manage the stairs and needed special handles in the bathroom and didnt want to go anywhere where there might be stairs and might not be special handles in the bathroom.

Her physical world got smaller and more frightening and then the world in her head got smaller and more frightening and the last few years were hard on everyone but especially her and my mother, who was taking care of her. So its not death I fear but decline, and while I know that plenty of people live long and happy and useful lives without ever running or even walking, that good lives happen in all kinds of bodies using all kinds of aids; while I know that health and strength in old age are partly matters of luck, I also observe as my parents generation ages that theres a lot a person in midlife can do to change the odds.

Also, it turns out, I like running. That is an understatement. I like running the way some people like heroin. I dont know if theres any physiological basis for talking about a running addiction, but I cant function without running at least a few miles a few times a week and preferably at least ten miles a day. Well, ten or fifteen, or sometimes eighteen if the light on the sea is good and my knees are holding up. I understand that running ten miles a day isnt the best way to train your body to go fast, and also that theres a high risk of injury in running that kind of mileage on asphalt month after month, and also that there should be rest days for soft tissue repair, but Im not particularly interested in going fast and Ive been doing it for years without injury and my soft tissue seems to be in adequate working order, not that there isnt a bit of pain from time to time but nothing consistent, nothing that seems like a reason to stop or even pause.

And is that when you think about your books, people ask, which is a nice idea, that all that time is really work, that hour and a half every day plus changing and showering plus core strength routine because thats why I dont get injured, but its not. If Im writing or about to write, I think about my book almost all the time except when Im running or knitting. I listen to podcasts, mostly science and medicine, while I run. I watch films, preferably in French or German, while I knit, or I talk to friends because I cant sit unless Im knitting or eating or teaching or reading but even for reading I prefer to pace the room and if we had space and I had the nerve Id buy one of those treadmill desks, though if I did that it would be only a matter of time before I tried running while knitting while watching a film in German. (I have just stopped writing this to make sure I still cant afford a treadmill desk, which isnt even really the main obstacle. I would need to check that I still cant afford a house big enough for a room of my own in which I could put a treadmill desk, and I live in Dublin so I know the answer to that.)

You relax, a psychologist friend observed, by hyperstimulation. I think of it as layering: if theres only one distraction, it might stop, but if I have three things going on even if one of them stops the other two will catch me. Its like the Swiss cheese theory of plane crashes: with enough layers of safety provision, the holes should never line up. If one engine fails, you can land with the other. My ideal form of relaxation, what Ill aim for if I have an evening alone in a hotel room, is knitting lace from a Japanese pattern while watching a film in French and also eating chocolate mousse with a very small spoon, and in the morning Id like to run a hilly route across a beautiful landscape while listening to a scientific researcher explaining her latest experiment. Its the rhythm, I say defensively, knitting is running for your fingers and you get a sweater at the end, but often the sweater is incidental.

I like interesting constructions (thats why I tend towards Japanese patterns) and I love the colors and textures of yarn and I enjoy knitting complicated lace, but in practice like everyone else I mostly wear plain things in shades of grey, which are deeply boring to knit. Im not running to maximize fitnessId run differently if I wereand Im not knitting to wear the clothesId knit differently if I were. Im keeping everything spinning, the dance of fingers and feet set to the rhythm of the heart and lungs, the minds pace set by footsteps and stitches, beating and pacing, being alive. I dont think it has anything to do with writing.

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The Fell by Sarah Moss is available via Farrar, Straus and Giroux.

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Actually, Not Everything is Writing: Sarah Moss on Why She Likes to Knit and Run - Literary Hub

In addition to trying to steal the history of medicine, Carmen has also attempted to plunder the concept of language, which would plunge the world into total chaos. The 1997 computer game "Carmen Sandiego: Word Detective" saw Carmen invent a device known as the Babble-On Machine, which instantly turns language into unintelligible gibberish. Carmen's ultimate goal in "Word Detective" is to render the world illiterate, with only the player character, Agent 13, able to stop her by reversing the machine's effects.

By the time "Word Detective" was released, the Carmen Sandiego franchise was already veering into more outlandish premises, completely abandoning narrative logic in favor of paper-thin plots to accommodate the educational content presented. Having said all that, the idea of Carmen stealing the concept of language itself just doesn't make any sense: If Carmen got into a life of crime for the professional challenge, eliminating language to make pulling off thefts easier directly contradicts this motivation.

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Things Only Adults Notice In Carmen Sandiego - Looper