Loss After Loss

The Essence of the Thing

As most often now, Ken was sleeping when I entered his room.  He opened his eyes, said hello, and dozed off again.  This is how our visits most often go.  I watched him for a while, quiet.  I sometimes wonder if he will be surprised to see me there when he opens his eyes again.  Maybe he is, but doesn’t say so.  Or maybe he’s not.  

He woke again and said, alarmed, I thought even frightened, "Have I been asleep for a day and a  half?"  I said no.  "Weeks?" he asked, more alarmed.  I hadn't seen him frightened before.  Unhappy to be where he is, yes, but not frightened.  

He closed his eyes again, and when he opened them, he asked, again sounding frightened, "Why did you let me sleep through the war?" I asked him which war, and he said, "The war with Russia.  Weren't we bombing Russia?" 

This hadn't been a dream.  Or, if it had been, it wasn't that he was still caught up in it.  Ken has dementia and lives in a memory care facility now.  He had forgotten the question soon after he asked it -- another brief moment in his now fleeting reality.  

A pencil drawing of Ken's hands that I did before I moved him into care. 

Ken was a brilliant man whose sharp mind and insightfulness gave him enormous pleasure and  satisfaction, and made it rewarding and satisfying to talk with him on almost any subject.  Many of us who love him miss those conversations most.  I hasten to add that having been brilliant doesn't make his dementia any more tragic than anyone else's.  If he'd been a great chef, we'd miss the meals, and the pleasure he took in preparing them. If he'd been a good mechanic, it would be painfully difficult to now have to take our cars to the shop.  But perhaps because we all valued Ken's brain so much, the slow disappearance of the very thing that gave him so much pleasure, and that we held in such high esteem, feels especially sad and poignant.  

We think of dementia as memory loss, but the losses are much greater than that.  Dementia is being lost in time and space, it’s loss of the ability to reason, to evaluate, to put two and two together, it’s truly living in the moment, which brings the loss of the ability to read, or to appreciate baseball games, or to grasp a film, because you need to bring the past with you to understand what’s happening now, or what comes next, even when that past is only moments ago. Dementia is the loss of the ability to calm yourself, to entertain yourself, to even care about entertaining yourself. It's the loss of the ability to learn, to make new memories. It’s personality loss, it’s the loss of self. For those of us who love someone with dementia, it’s the loss of the person we love.  

When Ken woke again, he said, “I wish I wanted to go home.”  He had never put it this way before.  I took it as a version of, “If I were home I wouldn’t feel as safe as I do here,” which he has said from time to time, and which I'm always comforted to hear, even though it's a thought that leaves him as quickly as it arrives. And, I haven't heard it in a while now. He sometimes knows he's in a retirement facility of some sort, but he has no insight into his dementia, so he doesn't know why he's there and not at home with me.  This lack of insight in people with dementia is much more common than understanding, and I feel fortunate that at least he doesn't have to cope with the loss himself, because that can be very painful.  He'll often say, "I don't even know why I'm here."  He once asked if it was because of the sore toe he had at the time.

Then, a moment later, “When can I go home?”  Had he changed his mind and now wanted to come home?  No, I don’t think that changing his mind is something he has any control over any longer.  Dementia runs things now.  He lives almost entirely in the moment, and what he’s thinking requires no work on his part.  I envision each moment passing, unremembered, and unconnected to the next. I answered, as I usually do, that we don’t know. 

And then he asked, as he always does repeatedly, and I never am, “Are you here for lunch?”  He has lost his sense of time of day.  He no longer remembers whether he’s had breakfast, or which meal is coming up.  He often seems disturbed about any meal, though, unsure of whether he wants it or not.  If I’m there before lunch, as I usually am, he’ll say he doesn’t want to go.  But then he’ll worry about what happens if he gets hungry later.  Maybe he can go get some chocolate milk. So, no, he won't go.  But then, when an aide comes to tell him it’s lunchtime, he goes.   

Still, after almost two years, he will ask me whether they bring meals to him in his room, or if he goes to the dining room. Then he'll ask if it's cafeteria-style, or the meals are served.  He once described getting to the cafeteria by walking down a long hall with pots and pans hanging on the walls. I don't know where that image came from.  It could be someplace from the past or it could be an invention.  But here it's a dining room where people are served at their tables.  No standing, no making decisions about what to eat.  

His confusion about this happens so often, probably before every meal, that I have come to imagine that all that's left of all the meals he’s ever eaten — at home, at restaurants, in hospitals or cafeterias — in whatever part of his brain they are still stored in, is a kind of Platonic ideal, the true, philosophical, non-physical essence of the thing that is Meal.  Or Meals. Now, multiple equally plausible images of mealdom -- whether self-selected in a cafeteria, a hospital tray brought to him in bed, or a dinner plate served at the table -- are still accessible to him.  But, he can’t settle on just one because he has essentially not been making new memories since long before memory care, so he doesn’t know where he is, or how he gets his meal, but he does still have, somewhere deep in the part of his brain that generalizes about life, that apparently can still generalize about life, images of the possible ways that a meal might appear before him. At some point, of course, this, too, will disappear. 

He still carries his wallet in his pants pocket, and wears his cell phone on his belt.  He won’t leave his room without either of them.  For a long time, there was only an expired driver’s license in his wallet, but then he lost that wallet, so I bought a new one, printed out a scan of the first page of his expired passport because I didn't have an image of his license, and images of his insurance cards and loaded those into the new wallet. I wasn't sure I even needed to do that, but when I gave it to him, he did check to make sure there was something in it. Happily, he was satisfied with what he saw.  

I cancelled his phone line a few months after he had forgotten how to turn the phone on, which was not long after he no longer knew how to answer it.  So, neither his wallet nor his phone any longer perform their primary functions — he has no credit cards, no money, no valid id, and he can’t make a phone call.  But to Ken, they have quite literally become their Platonic ideal, and that’s what counts now. They bring him security and comfort.  When he gets ready to leave his room, he goes through the same motions he's gone through for much of his life -- wallet, phone, pen, paper, (he no longer checks for his keys), ok to go down to the dining room, or cafeteria, to either choose my meal or be served. I have come to admire his courage for venturing into the unknown at least three times a day.  

Old Age is Loss After Loss

As an academic, and even after he retired, Ken lived on his email account, and took care of most of his business this way.  He was known for replying instantly to any message.  People worried when he didn’t.  He was a researcher, he was on a number of editorial boards, he was a department head, a professor, a collaborator, a parent, a friend, and he had extensive correspondences in all of those roles.  He organized his email by maybe 50 different labels and sublabels; Editorships, then Reviewing, or Personal, then Letters, for example, and he had tens of thousands of messages going back many years.  

A few years before I moved Ken to memory care, when he was still active on email but already having a bit of trouble figuring out how to use it, I was helping him with something, and I had to get into his account. I clicked on one of his labels, maybe Editorships, and then Reviewing, and discovered that there was nothing there, not a single message.  I clicked on other labels and found nothing under any of them, either.  All I could find were some messages in his inbox.  He had, surely inadvertently, deleted years and years of correspondence, all of which he’d carefully curated and saved — for what?  For later?  

I found this to be both deeply disturbing, and deeply profound.  On the one hand, years of back and forth collaborations, chatty messages from his children, his thoughts on academic papers he’d been asked to review, or reviews of papers of his own, correspondence with students and ex-students — so much of his life — gone in an instant, by the mistaken touch of a key on a keyboard. 

On the other hand, what had he been saving it all for?  He had never expressed any interest in writing his memoirs — if pressed to say what had been the most interesting parts of his life, I think he’d have said the world of ideas, and his own could already be found in his books and papers.  And, no one was going to write his biography, so what did it matter that it was all gone now?  He, to whom it should have mattered the most, wasn’t even aware that it had happened, so why should it matter to me?  

The digital evidence of our lives has become as real as the physical.  To me, this was a small death, one of the first in what’s turning into a long string of small deaths.  Indeed, dementia is sometimes known as "the long goodbye."  Loss after loss.  

That Question

I think Ken still has a Platonic ideal of Day in his head, too. Wake up, have breakfast, do stuff, have lunch, do stuff, have dinner, shower, go to bed.  Now, for "stuff" read "take nap." He no longer does anything but nap without prompting, and sometimes not even then. I think this might be because, in the map of Day in his head, he's already done whatever it is he's being asked to do. Or he will do it later, he really will. So, it's hard to convince him to take a shower because he is certain that he either already has taken one, or that he will.  Just like in his old reality.  

But, the other day I managed to talk him into showering, and I was helping him get ready.  He took off his shirt and I noticed he had a bandaid on his wrist.  I thought perhaps he’d had blood drawn, though they usually inform me when that happens and I’d heard nothing about it.  But, if so, I assumed he would no longer need the bandage so I suggested he take it off. It turned out that he had a jagged cut, now healing, on his fragile skin, definitely not a blood draw.  It looked superficial but had clearly bled a lot.  He, of course, had no idea what had happened and unless I happen to run into the aide who helped him clean it, I’ll never know. 

But, it doesn’t matter.  I put on another bandaid, the wound will heal and he’ll be fine. But, I wonder every day whether there will come a time when the intensity of the guilt and grief that has weighed me down since I moved him into care will abate.  This incident told me something about that.  

People often ask, “Does he still know you?”  This is a real question, yes, and it’s definitely a big deal line to cross.  But, it is also superficial in a way, since so much must already be lost before that point is reached.  Indeed, years usually go by between the onset of dementia and this, but everything that happens before that will have been just as hard as the loss of the person’s memory of those they love.  Or at least I think that’s true. The first time he forgot what to say when he answered the phone, and then how to answer the phone; the first time he forgot whether it was breakfast time or lunch time; when he couldn't remember whether I was with him in England in the Air Force or not (I wasn't), these were all difficult, and there's a new difficult thing almost every day.  So, I don’t know what it will feel like the first time he forgets me because we aren't there yet, but maybe it's a feeling I already know.   

I have always assumed that the complexity of the connection I feel to Ken will lessen when he no longer knows me. I suspect that I'll gain a bit of anonymity that will mean he will no longer be expecting Anne things from me.  It turns out that, for me, the discovery of a wound that I hadn’t known about, hadn’t discovered, hadn’t washed, and hadn’t bandaged, may have given me the sense of how this is going to feel.  I know that when he was looking for someone to help take care of the wound, if he was, it wasn’t me he was looking for.  And I know that he had no idea the he had a bandage on his arm 2 minutes after it was placed there, so even if I had been the one who had placed it there, he wouldn’t have remembered, and the fact that I had helped him would no longer mean anything to him.  

Ken won’t go to bed one night fully aware of who I am, and wake up the following morning having forgotten.  It’s a gradual process which I can already see happening. It’s been happening for years.  He still tells me he loves me, and he is still pleased to see me when I visit.  Though, the other day he said, “We’re married, aren’t we?”  It was impossible to know what prompted this — his head had taken him back to when we were together but not yet married?  He wasn't remembering that I was his wife?  I will never know, and whatever the reason, it was fleeting.  

I may feel differently when he no longer knows me, but I now think that forgetting what happened two minutes ago, or no longer sharing my reality, are as deeply significant in their way as his no longer knowing who I am will be. In significant ways, I am already as temporary, as easily wiped from his mind as the wound that required a bandage — already out of sight, out of mind.  Just not yet completely.  

Reality, Now and Then

A few weeks ago, the wife of a resident who Ken has sat with at meals every day since he’s been in memory care texted me while she was sitting with them at lunch.  I had been visiting, and then, as always, I walked Ken to the dining room, said goodbye and left. This woman, who has become a good friend as we both deal with husbands with dementia, texted five minutes later to tell me that Ken had just told her that I was in North Carolina with our daughter.  Later, he told her that I was in Europe.  And recently, he asked me if I’ve moved yet.  I asked where I was moving to.  He said he thought I was moving to North Carolina. 

Does he feel I’ve abandoned him? Or would? I have certainly learned that just because something makes sense to me, in my brain not being destroyed by dementia, that tells me nothing about what now makes sense to him. I don’t see him when I’m not there, so I can’t know, but he doesn’t seem to feel abandoned.  For him, when I'm there, I'm there.  When I'm not, I'm not; I'm who knows where. He seems to live in both realities as though both are always true.  That is, he truly lives in the moment, each moment his current reality. 

A few years ago, I decided to draw my completely invented idea of what happens to a brain with dementia.  I envision a very slow melting of the lobes.  I did this with Procreate. 

I’ve heard Ken say, when asked about the genetics research he used to do — which he no longer reliably remembers — that he ran a grasshopper lab, a fruit fly lab, studied intestinal diseases, or memory in WWII veterans at Walter Reed Hospital who’d lost half their brain.  None of this happened. He’s not just forgetting his career, he’s inventing alternatives.  He doesn't talk about Penn State or his career anymore. He was there for 35 years, but a year ago or so when we did talk about it, he remembered it as maybe 7.  His 5 years in the Air Force as a meteorologist when he was in his 20s are more real to him now than his long and successful career.  This isn't a surprise because, for people with dementia, earlier memories last longer. Even his Air Force memories are fading now, though.  

He has told stories of having worked in a bookmobile above the Arctic Circle in Finland during winter, he’s had sabbaticals in places he’s never been, he’s made his children’s travels his own, and even been down to see the Titanic.  All of this is confabulation, and it’s common with dementia.   

There has been disagreement in dementia care over the years as to whether it's better to go along with these kinds of stories or, instead, try to pull the person back into our own reality.  Their old reality.  There is now general consensus that no reminders, no amount of impatience, or scolding, or yelling, or arguing, can change the reality of someone with dementia.  It's better for everyone if we meet them where they are. I find that trying on the idea that their reality feels the same to them as it ever did makes this easier.  Plus, emotions seem to linger when words don't, so the attempt to remind someone of what we know to be true, but they no longer do, can cause more harm than good.  Of course it's painful to see someone lose what we had with them.  But, that is the nature of the disease.  

Ken sometimes asks why he's where he is now, and I always find this difficult to answer.  Dementia care workers often recommend the use of "therapeutic fibs" for situations like this.  I am completely fine with this, but I can't always think fast enough to come up with one and so occasionally I have told him that he's got memory issues.  He is always surprised.  I have asked if that seems true to him and he says no, even as his reality diverges further and further from mine, and from what it used to be, an ever-growing schism in what was once our shared world. 

Much of what happens in the mind of someone with dementia seems hard to understand. What is it like not to be able to follow the plot line of a book or a movie, or to not remember something for 2 minutes, or to be so distant from a reality we once shared with people we love that we can invent stories with abandon but not know it, or to forget people we once knew intimately and loved, and then to have no idea that our memory now works this way? 

Confabulation might be easier to understand. I think we've all had the experience of absolutely knowing that something happened, being certain of a memory, but then being told convincingly that we are wrong. It could be a memory that we've held on to for decades.  We might even have clear images in our heads. Indeed, we are all susceptible to the creation of false memories, through suggestion or misinformation, or these memories might simply be the product of our own imagination.  We've all unintentionally confabulated.  Our memories, even at their best, are not infallible.  

And, given that we can recognize that we might have this in common with people with dementia, it might require us taking just a few more conceptual steps to recognize that, for people with memory loss who don't have insight into their disease, what looks to us like a very foreign new reality doesn't feel new or strange to them at all. They don't know that their brains aren't working as they used to. So, while forgetting people they once loved is painful for those who've been forgotten, it's simply reality for the person who's forgetting.  Indeed, every time they see the people they once loved it can be like meeting someone for the first time, something we all recognize.  Reality itself has become a Platonic ideal.

Is it Ok to Publish This?

I write this post for people who've known Ken for a long time or who knew him only through this blog, or through his published work, or maybe who had him as a professor, but I also hope that what I have written here will mean something to people who've never heard of Ken Weiss before now, who haven't read any of his work, including the thousands of posts he published here on the Mermaid's Tale. Yes, it is said that if you've known one person with Alzheimer's disease, you've known one person with Alzheimer's disease, but I think there are aspects of the experience that can be generalized. 

 

I've been writing for years about Ken's Alzheimer's disease for myself and a few family members and close friends.  I have felt strongly about protecting his privacy, and because he can't give true informed consent, I've not wanted to write about his illness publicly.  But, not long ago, Ken asked what I do all day. I told him simply that I draw, I paint, and I write about what's happening to him.  He found that interesting. I asked if he thought I should blog about it, and he said yes.  This is certainly far from recognizable informed consent, given that he doesn't understand what's happening to him, but it's the closest thing I'm going to get from him. So, when Holly mentioned in her post last month that she'd gotten a book from me, I thought maybe it was time to explain. 

I now live alone, but I remain surrounded by Ken -- his clothes, his library, his CD's, his computer, his bike, his bike repair tools. I have been living as though he's going to recover and come home and pick up his life where he left off, but he isn't. The long goodbye.  

The old Ken is gone, and won't return, but there is still a Ken. There's no rush for me to empty my house of him, but could it help me accept the permanence of this disease if I started to work on it? A dear friend who was going through the very painful task of sorting through her wife's things after she died, very kindly offered to come help me sort through the clothes that Ken would no longer wear, whenever I was ready.  We did this, but I left the space we'd emptied empty.  I couldn't bring myself to use his side of the closet.  It wasn't until months later, when I had to clear out the entire closet because of work being done in the attic that was accessed from a hatch in the closet ceiling, that I could actually hang up my own clothes on "his" side when the work was finished.  

In the same spirit, Holly offered to come help me sort through his books.  I was so grateful for this, and it especially meant a lot to me to have so many of them going to her.  I know Ken would have approved. And, one of the books she chose to take was Fossil Men.  If you haven't read her post about this book, do!  Ken would have loved it!  

And, my daughter, who grieves those missing conversations with her father every day, has convinced me that he would have wanted his story written if there was any hope at all of someone else resonating with something we have learned along the way, perhaps learning from it, too. Dementia is a tragic disease, indeed a long goodbye. It's because it's so common that there are tremendous resources available to those of us living with it -- an amazing Alzheimer's Association social worker has called me at least every month for 5 years offering invaluable advice and support and care, a palliative care team was very helpful for a few years until I moved Ken into care, my sister has been invaluable, Ken's sister, many of the staff where he now lives have been kind and understanding, the wives of other residents in the memory care unit, women who understand what it means to lose a spouse this way, have been welcome fellow-travelers, dear friends have kept me standing upright, as has my daughter.

Dementia is a long hard haul.  It can break families, it can cause caregiver burn-out, it can deplete finances, and it always leaves much grief in its wake.  If there is anything I have said here that might lessen the burden for someone else dealing with this disease, even if it's just knowing that you are not alone, I am grateful. I choose to believe that my Platonic ideal of Ken would be grateful, too.  

Science journals: Anything for a headline

Well, this week's sensational result is reported in the Oct 5 Nature in a paper about limits to the human lifespan. The unsensational nature of this paper shows yet again how Nature and the other 'science' journals will take any paper that they can use for a cheap headline.  This paper claims that the human life span cannot exceed 115 (though the cover picture in a commentary in the same issue is a woman-- mentioned in the paper itself--who lived to be substantially older than that!).  The Nature issue has all the exciting details of this novel finding, which of course have been trumpeted by the story-hungry 'news' media.

In essence the authors argue that maximum longevity on a population basis has been increasing only very slowly or not at all over recent decades.  It is, one might say, approaching an asymptote of strong determination. They suggest that there is, as a result of many complex contributing factors-of-decline, essentially a limit to how long we can live, at least as a natural species without all sorts of genetic engineering.  In that sense, dreams of hugely extended life, even as a maximum (that is, if not for everyone), are just that: dreams.

This analysis raises several important issues, but largely ignores others.  First, however, it is important to note that virtually nothing in this paper, except some more recent data, is novel in any way.  The same issues were discussed at very great length long ago, as I know from my own experience.  I was involved in various aspects of the demography and genetics of aging, as far back as the 1970s.  There was a very active research community looking at issues such as species-specific 'maximum lifespan potential', with causal or correlated factors ranging from the effects of basic metabolism, or body or brain size.  Here's a figure from 1978 that I used in a 1989 paper




There was experimental research on this including life-extension studies (e.g., dietary restriction) as well as comparison of data over time, much as (for its time) the new paper.  The idea that there was an effective limit to human lifespan (and likewise for any species) was completely standard at that time, and how much this could be changed by modern technologies and health care etc. was debated. In 1975, for example (and that was over 40 years ago!), Richard Cutler argued in PNAS that various factors constrained maximum lifespan in a species-related way.  The idea, and one I also wrote a lot about in the long-ago past, is that longevity is related to surviving the plethora of biological decay processes, including mutation, and that would lead to a statistical asymptote in lifespan.  That is, that lifespan was largely a statistical result rather than a deterministically specified value.  The mortality results related to lifespan were not about 'lifespan' causation per se, but were just the array of diseases (diabetes, cancer, heart disease, etc.) that arose as a result of the various decays that led to risk increasing with duration of exposure, wear and tear, and so on, and hence were correlated with age.  Survival to a given age was the probability of not succumbing to any of these causes by that age.

This paper of mine (mentioned above) was about the nature of arguments for a causally rather that statistically determined lifespan limit.  If that were so, then all the known diseases, like heart disease, diabetes, cancer, and so on, were irrelevant to our supposed built-in lifespan limit!  That makes no evolutionary sense, since evolution would not be able to work on such a limit (nobody's still reproducing anywhere near that old).  It would make no other kind of sense, either.  What would determine such a limit and how could it have evolved?  On the other hand, if diseases--the real causes that end individual lives--were, together, responsible for the distribution of lifespan lengths, then a statistical rather than deterministic end is what's real.  The new paper doesn't deal with these, but by arguing that there is some sort of asymptotic limit, it implicitly invokes some sort of causal, evolutionarily determined value, and that seems implausible.

Indeed, evolutionary biologists have long argued that evolution would produce 'negative pleiotropy', in which genomes would confer greater survival at young ages, even if the result was at the expense of greater mortality later on.  That way, the species' members could live to reproduce (at least, if they survived developmentally-related infant mortality), and they were dispensable at older ages so that there was no evolutionary pressure to live longer.   But that would leave old-age longevity to statistical decay processes, not some built-in limit.

Of course, with very large data sets and mortality a multicausal statistical process, rare outliers would be seen, so that more data meant longer maximum survival 'potential' (assuming everyone in a species somehow had that potential, clearly a fiction given genetic diseases and the like that affect individuals differently).  There were many problems with these views, and many have since tried to find single-cause lifespan-determining factors (like telomere decay, in our chromosomes), an active area of research (more on that below).  We still hunger for the Fountain of Youth--the single cause or cure that will immortalize us!

The point here is that the new paper is at most a capable but modest update of what was already known long ago.  It doesn't really address the more substantive issues, like those I mention above.  It is not a major finding, and its claims are also in a sense naive, since future improvements in health and lifestyles that we don't have now but that applied to our whole population could extend life expectancy--the average age at death--and hence the maximum to which anyone would survive. After all, when we had huge infectious disease loads, hardly anybody lived to 115, and in the old days of research, to which the authors seem oblivious, something like 90-100 was assumed to be our deadline.

The new paper has been criticized by a few investigators, as seen in reports in the news media coverage.  But the paper's authors probably are right that nothing foreseeable will make a truly huge change in maximum survival, nor will many survive to such an extended age.  Nor--importantly--does this mean that those who do luck out are actually very lucky: the last few years or decades of decrepitude may not be worth it to most who last to the purported limit. To think of this as more than a statistical result is a mistake.  Not everyone can live to any particular age, obviously.

The main fault in the paper in my view is the claim in essence to portray the result as a new finding, and the publication in a purportedly major journal, with the typical media ballyhoo suggesting that.

On the other hand....
On the other hand, investigators who were interviewed about this study (to give it 'balance'!) denigrated it, saying that novel medical or other (genetic?) interventions could make major changes in human longevity.  This has of course happened in the past century or two.  More medical intervention, antibiotics and vaccines and so on have greatly increased average lifespan and, in so doing in large populations, increased the maximum survival that we observe.  This latter is a statistical result of the probabilistic nature of degenerative processes like accumulating wear and tear or mutations, as I mentioned earlier.  There is no automatic reason that major changes in life-extending technologies are in the offing, but of course it can't be denied as a possibility either. Similarly, if, say, antibiotic resistance becomes so widespread that infectious diseases are once again a major cause of death in rich countries, our 'maximum lifespan' will start to look younger.

Those who argue against this paper's assertions of a limit must be viewed just as critically as they judged the new paper.  The US National Institute on Aging, among other agencies, spends quite a lot of your money on aging, including decades (I know because I had some of it) on lifespan determination.  If someone quoted as dissing the new 'finding' is heavily engaged in the funding from NIA and elsewhere, one must ask whether s/he is defending a funding trough: if it's hopeless to think we'll make major longevity differences, why not close down their labs and instead spend the funding on something that's actually useful for society?

There are still many curious aspects of lifespan distributions, such as why rodents have small bodies that should be less vulnerable per-year to cancer or telomere degradation etc. that relate to the number of at-risk cells, yet only live a few years.  Why hasn't evolution led us to be in prime health for decades longer than we are?  There are potential answers to such questions, but mechanisms are not well understood, and the whole concept of a fixed lifespan (rather than a statistical one) is poorly constructed.

Still, everything suggests that, without major new interventions that probably will, at best, be for the rich only, there are rough limits to how long anyone can statistically avoid the range of independent risk our various organ systems face, not to  mention surviving in a sea of decrepitude.

One thing that does seem to be getting rather old, is the relentless hyperbole of the media including pop-culture journals like Nature and Science, selling non-stories as revolutionary new findings.  If we want to make life better for everyone, not just researchers and journals, we could spend our resources more equitably on quality of life, and our research resources on devastating diseases that strike early in the lives we already are fortunate to have.

Cancer moonshot and slow-learners

Motivated by Vice President Biden's son's death at an early age from cancer, President Obama recently announced a new health initiative which he's calling the cancer 'moonshot'.  This is like a second Nixonian 'war' on cancer but using a seemingly more benign metaphor (though cancer is so awful that treating it as a 'war' seems apt in that sense). Last week the NYTimes printed an op-ed piece that pointed out one of the major issues and illusions belied by the rhetoric of the new attack on cancer, as with the old:  Curing one cancer may extend a person's life, but it also increases his or her chances of a second cancer, since risks of cancer rise with age.

Cancers 'compete' with each other for our lives
The op-ed's main point is that the more earlier onset cancers we cure, the more late onset, less tractable tumors we'll see.  In that sense, cancers 'compete' with each other for our lives.  The first occurrence would get us unless the medical establishment stops it, thus opening the door for some subsequent Rogue Cell to generate a new tumor at some later time in the person's life.  It is entirely right and appropriate in every way to point this out, but the issues are subtle (though not at all secret).

First, the risk of some cancers slows with age.  Under normal environmental conditions, cancers increase in frequency with age because they are generally due to the accumulation of multiple mutations of various sorts, so that the more cell-years of exposure the more mutations that will arise.  At some point, one of our billions of cells acquires a set of mutational changes that lead it to stop obeying the rules of restraint in form and cell-division that are appropriate for the normal function of its particular tissue. A tumor is a combination of exposure to mutagens and mutations that occur simply by DNA replication errors--totally chance events--when cells divide.  As the tumor grows it acquires further mutations that lead it to spread or resist chemotherapy etc.

This is important but the reasons are subtle.  The attack on cells by lifestyle-related mutagens like radiation or chemicals in the environment becomes reduced in intensity as people age and simplify their lives, slowing down a lot of exposures to these risk factors. However, cell division rates, the times when mutations arise, themselves slow down, so the rate of accumulation of new mutations, whether they be by chance or by exposures, slows.  This decrease in the increase of risk with age at least tempers the caution that curing cancers in adults will leave them alive for many years and hence at risk for at least some many more cancers (though surely it will make them vulnerable to some!)

Apollo 11, first rocket to land humans on the moon; Wikipedia

Competing causes: more to the story, but nothing at all new
There's an important issue not mentioned in the article, but that is much more important in an indirect way.  This is an issue the authors of the op-ed didn't think about or for some reason didn't mention or perhaps because they are specialists they just weren't aware of.  But it's not at all secret, and indeed is something we ourselves studied for many years, and we've blogged about here before: anything that reduces early onset diseases increases the number of late onset diseases.  So, curing cancer early on (which is what the op-ed was about) increases risk for every later-onset disease, not just cancer.  In the same way as we've noted before, reducing heart disease or auto accident rates or snake bite deaths will increase dementia, heart disease, diabetes, and cancer--all other later-onset diseases--simply because more people will live to be at risk.  This is the Catch-22 of biomedical intervention.

In this sense all the marketing rhetoric about 'precision' genomic medicine is playing a game with the public, and the game is for money--research money among other things.  There's no cure for mortality or the reality of aging.  Whether due to genetic variants or lifestyle, we are at increasing risk for the panoply of diseases as we age, simply because exposure durations increase.  And every victory of medicine at earlier ages is a defeat for late-age experience.  Even were we to suppose that massive CRISPRization could cure every disease as it arose, and people's functions didn't diminish with age, the world would be so massively overpopulated as to make ghastly science fiction movies seem like Bugs Bunny cartoons.

But the conundrum is that because of the obvious and understandable fact that nobody wants major early onset diseases, it seems wholly reasonable to attack them with all the research and therapeutic vigor at our disposal. The earlier and more severe, the greater the gain in satisfactory life-years that will be made.  But the huge investment that NIH and their universities clients make in genomics and you-name-it related to late-age diseases is almost sure to backfire in these ways.  Cancer is but one example.

People should be aware of these things.  The statistical aspects of competing causes have long been part of demographic and public health theory.  Even early in the computer era many leading demographers were working on the quantitative implications of competing causes of death and disease, and similar points were very clear at the time.  The relevance to cancer, as outlined above, was also obvious.  I know this first-hand, because I was involved in this myself early in my career.  It was an important part of theorizing, superficial as well as thoughtful, about the nature of aging and species-specific lifespan, and much else.  The hard realities of competing causes have been part of the actuarial field since, well, more or less since the actuarial field began.  It is a sober lesson that apparently nobody wants to hear.  So it should not be written about as if it were a surprise, or a new discovery or realization.  Instead, the question--and it is in every way a fair question--should be why we cannot digest this lesson.  Is it because of our normal human frailty wishful thinking about death and disease, or because it is not convenient for the biomedical industries to recognize this sober reality front and center?

It's hard to accept mortality and that life is finite.  Some people want to live as long as possible, no matter the state of their health, and will reach for any life-raft at any age when we're ill.  But a growing number are signing Do Not Resuscitate documents, and the hospice movement, to aid those with terminal conditions who want to die in peace rather than wired to a hospital bed, continues to grow.  None of us wants a society like that in Anthony Trollope's 1881 dystopic novel The Fixed Period, where at age 67 everyone is given a nice comfortable exit--at least that was the policy until it hit too close to home for those who legislated it.  But we don't want uncomforable, slow deaths, either.

The problem of competing causes is a serious but subtle one, but health policy should reflect the realities of life, and of death.  I wouldn't bet on it, however, because there is nothing to suggest that humans as a collective electorate are ready or able to face up to the facts, when golden promises are being made by legislators, bureaucrats, pharmas, and so on.  But, science and scientists should be devoted to truth, even when truth isn't convenient to their interests or for the public to hear.

The Elephant (not) in the Cancer Ward

Recently, Tomasetti and Vogelstein (the latter a senior and highly regarded cancer geneticist) suggested that most cancer is due just to bad luck.  We discussed that study here.  When cells divide, DNA is copied, but that is a molecular process that isn't perfect (see discussion of Wednesday's Nobel Prize in Chemistry, e.g., for the discovery of DNA repair mechanisms and their association with cancer).  There are mutation detection mechanisms of various sorts (the BRCA1 gene whose mutations are associated with breast and some other cancers, is one with that sort of function).  The more at-risk cell divisions, the more mutations, and the higher the likelihood that one cell will experience a combination of mutations that (along with inherited variation) transforms the cell into the founder of a cancer.  T and V's assertion based on statistical analysis of numbers of cells at risk, their division rate for given tissues, and age of onset patterns, was that random mutation was a major contributor to cancer, rather than inherited genotype or environmental exposures, which they argue would account for this substantial fraction of cases.

Naturally, those whose grant fortunes depending on the idea that cancer is 'genetic' and/or 'environmental' roared in opposition to an idea that could threaten their perspective (and empires). Some of the T and V paper's statistical methods were questioned, and perhaps their paper was over-stated or less definitive than claimed.  Nobody can doubt that genetic variation and environmental exposures that could cause cells to be more likely to experience mutations, play a role in cancer.  But in any practical sense, it is hard to deny that luck plays a role (even with environmental exposures, because if they cause mutations, they basically strew them randomly across the genome, rather than causing them in any particular gene, etc.).

But we mentioned an important issue then that had been raised 40 years ago by epidemiologist Richard Peto.  Essentially it is that other mammals, like mice, experience a similar array of cancer types, with similarly increasing risk with age....but that increase is roughly calibrated with their life span. In fact, mice have far fewer stem cells in, say, their intestine or blood than humans, but their risk of cancer in these tissues increases far more rapidly (in years) than does human risk, though we have orders of magnitude more at risk cells and cell divisions.  This became known as Peto's Paradox.  It has not really been answered though there are some attempts to determine how it is that different species, of different sizes, calibrate their cancer risk in relation to their observed typical lifespan.

"Elephas maximus (Bandipur)" by Yathin S Krishnappa - Own work. Licensed under CC BY-SA 3.0 via Commons - 

For example a 2014 paper in Nature Reviews Genetics by Gorbunova et al. documents the very different typical lifespans of rodent species, and suggests some plausible genetic mechanisms that may protect the longer-lived species from cancer.  There must be some such mechanism, or else we misunderstand something very important in the carcinogenesis process.

Now a new commentary has been discussed in the NY Times of a JAMA paper, that makes similar genetic arguments for the very out-of-line cancer-free longevity of elephants.  Based on their numbers of at-risk cells, elephants should drop over with cancer at a very young age, but instead they typically live for a very long time.  How can this be?

The JAMA authors, Abegglen et al., found that a gene, called TP53, that is clearly related (when mutated) to cancer susceptibility in humans and in experimental assays, at least in part because it detects and effectively kills misbehaving mutated cells.  The study included humans with Li Fraumeni syndrome (LFS), a genetic disorder that greatly increases the risk of developing cancer, susceptibility to which has long been known to be associated with variants in TP53, and blood samples from Asian and African elephants.  

The study needs close scrutiny for methodological issues, but the authors make what they feel, reasonably, is a relevant finding.  There is only one copy of the TP53 gene in humans, but in elephants there are 20.  In blood cell assays this gene's activity was higher than in humans.  The inference is that elephants' longevity relative to cancer is due to this gene. If that is indeed the (or at least, an) explanation for the elephants' cancer-related longevity, it raises some other important questions, which should at least raise eyebrows and the need for ever-present skepticism.

Questions raised by the results
As in the rodent paper cited above, single-gene mechanisms for complex traits are appealing and publication-worthy, but in a sense such claims raise questions about themselves.  Elephants live long lives relative to other diseases that essentially have little if anything to do with cancer.  One can think of heart disease, dementia, stroke, kidney failure, liver disease, neuromuscular and joint disease, and waning immune systems.  Are these traits all due to having more TP53?  That seems unlikely.  

Alternatively, apparently whales are known not to have multiple TP53 duplicates, and I don't know about other very large animals like rhinos, giraffes, and so on.  A standard argument would be that in ecological circumstances when natural selection favors longer lives for some species, it uses whatever mechanism happens to be available--that is, selection has no foresight and can't just choose genes to duplicate.  Each species will have experienced the longevity advantage in its own local time, place, and ecosystem.  Just as the genes whose mutation yields resistance to malaria in humans vary from continent to continent, so will longevity-related genes favored by selection

So, Peto's Paradox remains curious.  If each species has its own protective mechanism (and perhaps several for its different organ and physiological systems), then we can account in a reasonable way for longevity patterns.  There is no need to find, or even to expect the same thing in all species' evolution: variation in response to selection can vary by organ system, species, and location even among species.  This is exactly the sort of thing that we should expect when we think of the complexity of genomic mechanisms--and what has consistently been found by genome mapping studies (GWAS) of late onset traits (and, for that matter, even early onset ones).

In turn, that means that each paper that claims subtly or overtly to have found 'the' or even a widespread important mechanism related to aging needs to be taken circumspectly.  Aging and lifespans are complex phenomena.  We will learn from each example we document, as with GWAS results, that a simple anti-aging strategy can't be inferred.  It's not likely to be a single magic bullet.

On Being Mortal

Ken and I have written a lot about disease causation, prediction and prevention but we haven't written much about the other side, when prediction, prevention and treatment aren't enough, when disease becomes fatal.  We have just read Dr Atul Gawande's book Being Mortal, a beautifully written heartfelt exploration of the end of life.  Dr Gawande is a surgeon at a major teaching hospital, and a professor of health policy, and his job is to save lives, and to teach medical students how to do the same.  He is presumably very good at this.  In the book, though, he writes about the process of learning how to be a doctor when there is no cure and he can't save a patient's life, something he didn't learn in school, and that has taken him decades to learn.  Presumably these are lessons he now teaches to his students, to the great benefit of us all.

Dr Gawande tells his story through many case histories, including that of his father, as he made decisions about how to live, and die, with an untreatable cancer.  He told some of these same stories in the BBC Reith Lectures last fall.  He writes about the tremendous regret he now has about instances in which he just was not able to have the kind of conversation with a dying patient that he now knows he should have had.

We are used to two common medical models, he says, the 'paternalistic' model of the 1960's, when a patient could be treated with a blue pill or a red pill, and the doctor made the choice. "Take the red pill.  It will do you good."  Then, the 'information' model took over -- the doctor supplied information, telling the patient that his/her disease could be treated with a blue pill or a red pill, explaining the pros and cons of each and then asking the patient to choose.  But, we don't face the end of our lives statistically, and weighing the pros and cons of different treatments is not what helps us make decisions about how to proceed, which is what Gawande finally realized after too many painful conversations with his very sick patients.

When terminally ill, a patient is overwhelmed with fears and concerns, and recognizing and acknowledging these is the truly important role a doctor can play when a patient is facing life-threatening illness. After much thought, hundreds of conversations with gerontologists, palliative care physicians, managers of the best assisted living facilities, and with patients, Gawande has come to see that there's another model, the 'interpretive' or 'shared decision making' model.

Gawande now asks his patients, What are your priorities if your time is limited?  What are your goals for treatment?  What are your fears?  And what trade-offs are you willing to accept as a result of your care?  And, he, the patient, and the patient's family choose the course of treatment with the patient's answers in mind.

One patient said that as long as he could watch football and eat chocolate ice-cream he wanted to keep living, so treatment continued for this man longer than it did for, for example, Gawande's father who said that he wanted not to suffer, did not want to be paralyzed, and if he couldn't enjoy seeing friends and family, he wanted no more treatment.  So, he refused further chemotherapy when the trade-offs were no longer acceptable to him.

In modern medicine, it's important to recognize that 'no cure' is not the same as 'no treatment'.  There is almost always something else that can be tried, some heroic measure, some experimental surgery or medicine that can be used to give a patient hope, or even a little more time, even when the illness can't be cured.  Doctors are very good at plugging ahead with all of this, without stopping to ask their patients the kinds of things that Gawande now asks.  The proper goal of the medical system, Gawande now believes, is not to stave off death as long as possible, or even to make a good death, but instead to assist in assuring "a good life to the very end."

According to Dr Gawande, modern medicine is very good at a lot of things, but preventing and treating aging and death are not among them.  Until the 1950's, people in the developed world most often died at home.  Then, increasingly, as it became more and more possible for medicine to intervene in the process, people began to die in hospital -- indeed, at ever increasing expense.  Now, however, people are beginning to choose to die at home again, and the hospice movement is largely responsible for making this work as well as it can.

The primary role of nursing homes (an industry which, according to Gawande, began to grow when the number of hospital beds for the elderly wasn't sufficient once aging and dying were medicalized) is to keep the elderly safe, but at the cost of lost privacy, dignity and control over one's own life. Nursing homes are run for the convenience of the system, not the residents. Fortunately, there are increasingly alternatives that allow people to 'age in place,' in their own homes, or if that's not possible, in an assisted living alternative, with as much or as little aid as they want or need.  

If Gawande's book is an indicator that we are wresting aging and dying back from a system that appropriated it, at great cost in money and suffering, it is reminiscent of the movement to demedicalize pregnancy and childbirth, with the increasing popularity of birthing centers and home births, or of menopause, which once meant hormone replacement therapy for all but no longer does.  There are many things modern medicine does very well, of course.  But there are things it can't and will never do well, including preventing aging and death.  

Still, many people do opt for heroic measures at the end of life.  This is in a sense because of the hope that they can be cured, and perhaps a deeper yearning for immortality.  Is this because medicine has over-promised?  Surely in part.  As Gawande says, patients are usually thinking in terms of 10 or 15 additional years when they hear that yet another treatment can be tried, not weeks or months, but it's more like weeks or months that these heroic measures have to offer.  

But this over-promising is nothing new.  Genetics has been doing it for decades, and the new commitment to precision medicine, genetics and so much more, is more of the same.  Some of this is because of snake oil salesmen, certainly, but not entirely.  Just as we have to blame Trump's popularity not just on Trump, but on the people buying his 'message' as well, it is the age of genetics because the people have bought the message being sold.  This isn't so different from the promise of miraculous cures by some religions (or mountebanks).

Surely there will come a time when we recognize that all that has been promised just can't be done, we won't be able to foretell our medical, academic, economic, or romantic futures from our genomes at birth,  and we'll understand that geneticizing our lives is as much over-promising as is the idea that one more experimental chemotherapy is going to finally cure our incurable disease.    

We put our faith in medicine when we are most vulnerable, hoping against hope that it will save us.  Perhaps it was the miracle drugs of the mid 19th century that encouraged this faith -- antibiotics really did save lives.  And then technology -- kidney dialysis and heart transplants, hip replacements and triple bypass surgeries.  We're very good at technology.  But, we still don't really understand cancer, or mental illnesses, or the cause of so many diseases.  And we won't be able to predict complex disease from our genes (which we've written about many times before on the MT), and we certainly can't prevent aging or death.  Despite the promises.  

Atul Gawande's message is sane and oddly reassuring, but as such it's a radical one as he aims to return control of a patient's present and future back to the patient.  This is a challenge to vested interests, yes, as well as a challenge to the usual way medicine is done in the industrialized world.  But it's a welcome and important one, because it's something we all will face.

An age-old surprise....or not

Yesterday's Big Story of the microsecond on the BBC's web page was the profound discovery by scientists that people age at different rates. This in itself is something that has been so obvious that it hardly merits a sentence, much less a whole story.  But it is a news report of an actual science paper in the journal PNAS.  There are some interesting aspects that are worth discussing, but why is this paper in a major journal?

According to the paper, "Already, before midlife, individuals who were aging more rapidly were less physically able, showed cognitive decline and brain aging, self-reported worse health, and looked older." As a result, we've got a new 'science', ''geroscience' coined as mentioned by the authors, but this seems to be much more about marketing than actual science, because we already have fields known as gerontology, the biology of aging, and so on.

Still, an important health-related objective is to anticipate disease before it has occurred so that it can be prevented.  If signs of aging can be detected early, and there are interventions that may slow it--or, even just if the person could be advised of his/her state so s/he can live to the fullest--then this will be progress.  It is, of course, a main idea behind the notion of 'precision genomic medicine'.

This paper reports on a study of 38 year olds who had had some baseline measures of basic health taken at age 26, so it's a report of change over 12 years.  Measures of cardiovascular, metabolic, immune and other health-status were taken.  It isn't clearly stated in the paper that we can find, but these individuals were presumably all 'healthy' at the time of the study.  The paper shows that if typical health-related criteria are used, there is a normal (bell-shaped) curve of biological age among these 38 year olds, as shown here:

Source

Anyone knows, or should, that biological traits vary among individuals.  Most traits vary with age as experience, wear-and-tear, and so on occur.  Age-related variation can be because of genetic and/or environmental/lifestyle variation.  The normal distribution is so robust a general pattern of variation that its shape is no surprise either, and also not particularly informative per se, but it does reflect the fact that we vary in almost everything.

The different biological systems showed regular increases in average age-related measures over this 12-year period, as this figure, also from the paper, shows:

Again, there is absolutely no surprise in seeing that obvious age-related traits change with age on average.  But the authors also found that individuals who seemed biologically 'older' at age 38 had experienced greater age-related change in their systems over the 12-year period:

How risk factors affect risk
The notion that genetic or environmental risk factors raise risk is only part of the story.  Risk factors don't just change your risk.  Typically they change the 'hazard function', that is, the change of risk with time, that is, with age.  Exposure per dose-duration usually accelerates risk, often exponentially.  In other words, the more exposure the faster risk increases--the faster you 'age' with respect to when you may get the disease.

This is why, for example, those with high risk genetic factors usually are found initially by study of early onset cases of a given disorder.  Biological effects are ongoing and their effects, say tissue damage or somatic mutation, accumulate with exposure level and duration.

These generalizations have been known for many decades (I say this because even in the 1970's I was working on the biology and genetics of aging and these things were in the textbooks as well as research literature.  So it is not any sort of surprise to see the reported effects, and in that sense they should not have been treated as if they were new.  In essence, gradual risk increase with age is aging.)

This is not to say the results are wrong in any way, nor that following a cohort in this way is not useful.  The past literature dealt with multiple 'competing' causes in various ways, usually as if they were independent.  But it was of course known that if you were exposed to multiple risk factors then multiple causes would accelerate in risk and so on--as this paper reports.

Since we all vary in our genomes and in our lifestyle habits, our various systems will 'age' in ways that respond to those individual exposures.  Some factors seem to affect multiple tissues and their associated diseases (telomere shortening, for example, is argued by some to accelerate many different risks).  If we could identify the causes of these differences, we could in principle ameliorate them for the fast-agers. Then, of course, the 'geroscience' community would demand big studies to intervene in everyone, because even the slower agers could be made to age more slowly still.

We must also expect that when these measures are subjected to genomewide mapping---how could there not be a demand for funds to do this?--the traits will largely turn out to be genetically complex and rarely due to tractably simple genotypic variation.  Similarly, environmental/lifestyle variation will be shown to be important, if not the main factor, and we know how difficult such things are to change, or even to identify.

The authors clearly point out several limitations to this study, and do stress environmental factors that may be responsible and ascertainable.  They argue that animal models (such as mice, who are short-lived among other things) don't provide the kind of direct individual evidence we would like.  We already know of some specific genetic factors that accelerate what otherwise are age-related traits (people with Down Syndrome and other progerias show these symptoms, including bone, skin, and muscular effects), but it is debated whether these should properly be viewed as generic aging-related rather than simply tissue-specific effects of a given gene.  The 'pace of aging' in the above figure represents an average or total of the various measures.  So one needs to discern whether fast-agers in the PNAS study population were aging fast in all measures or just one or a few (and if the latter, were those measures related).

As with many things of this nature, a point we regularly note, relevant environmental factors may, if studies are lucky, be identified in retrospective studies like this one, but since we cannot predict lifestyles of the future, the studies may be interesting but often of unknowable relevance to people who are now young relative to their health futures.