If you had to summarise Seneca’s most uncomfortable observation in a single sentence, it would be this: most of what you are spending your life trying to acquire is not actually going to satisfy you when you get it. Lucius Annaeus Seneca, the Roman Stoic philosopher who served as tutor and later adviser to the Emperor Nero, wrote 124 surviving letters to a younger Roman official named Lucilius across the final years of his life — letters that have remained in continuous circulation for nearly 2,000 years and that contain some of the more concentrated observations of human psychology produced in the ancient world. Among the recurring themes in these letters is the curious gap between what people pursue and what actually makes them content. Seneca’s specific claim was that the pursuit of more — more wealth, more possessions, more recognition, more of essentially anything one could accumulate — does not converge on satisfaction. As the supply increases, the demand increases with it, and the gap between the two never closes.

According to the Internet Encyclopedia of Philosophy’s reference on Seneca, his writings repeatedly addressed this question across multiple letters and essays. “It is not the man who has too little, but the man who craves more, that is poor,” he wrote in his second letter to Lucilius. “Contented poverty,” he added, quoting his philosophical opponent Epicurus approvingly, “is an honourable estate.” In another letter, again quoting Epicurus: “Whoever does not regard what he has as most ample wealth, is unhappy, though he be master of the whole world.” Contentment, in Seneca’s account, is not a function of how much one has but of how little one needs. People who have learned to need less can be content with very little. People who have not can fail to be content with essentially anything.

The empirical convergence

For most of the period between Seneca’s death and the late twentieth century, his observations existed as philosophical claims — defensible by argument, supported by example, but unverifiable by anything resembling modern empirical methodology. This changed in 1971, when the psychologists Philip Brickman and Donald Campbell introduced into the social-science literature the concept of the “hedonic treadmill” — a model in which positive events produce short-term elevations in subjective well-being that fade over time as people adjust their expectations upward to match their new circumstances. The model predicted that lottery winners, despite their substantial good fortune, should not end up much happier than they were before winning, because their reference point would shift upward and their new wealth would come to feel normal rather than exceptional.

Per the Wikipedia reference on the hedonic treadmill and its empirical foundations, Brickman and his colleagues Dan Coates and Ronnie Janoff-Bulman tested this prediction directly in a now-famous 1978 study published in the Journal of Personality and Social Psychology. The research team compared 22 major lottery winners with 22 demographically matched controls and 29 individuals who had been paralysed in accidents. The results were striking. Lottery winners were not significantly happier than controls. They reported finding less pleasure in ordinary daily activities than non-winners did, suggesting that the peak experience of winning had contaminated their capacity for mundane satisfaction. The paralysed accident victims, while clearly less happy than controls, were closer to controls than would have been predicted by the magnitude of their loss. The basic Stoic claim — that the relationship between external circumstances and inner contentment is much weaker than ordinary intuition suggests — was, in its broad outlines, empirically confirmed.

Why the mechanism works

The mechanism Brickman and Campbell identified, which Seneca had described in different language, is that humans adjust their internal reference point as their external circumstances improve. The first car you own provides substantial improvement over having no car. By the time you have reached the tenth car in a lifetime of progressively improving vehicles, each new one barely registers, even though every one of them would have seemed luxurious to the person you were before you owned any. The same pattern applies to houses, salaries, food, clothing, professional recognition, and essentially every other category of acquirable good.

The economist Richard Easterlin documented the same pattern at the level of whole societies in 1974, in what has come to be called the Easterlin Paradox. Within any given country at any given moment, richer people report being happier than poorer ones. But as an entire country grows richer over decades — as per-capita income doubles, then triples, then quadruples — average happiness barely moves. The collective acquisition of more does not produce collective contentment. The individual aspiration level rises in parallel with collective wealth, and the gap between aspiration and achievement remains essentially constant.

The hypocrisy charge

The honest account of Seneca’s argument requires noting an awkward complication. Seneca himself was extraordinarily wealthy. He served as a senior adviser to Emperor Nero and accumulated, over the course of his career, a personal fortune estimated by Roman historians at approximately 300 million sesterces — making him one of the richer private citizens in the Roman Empire. He owned multiple villas, substantial estates, and significant financial holdings, including loans to provincial elites that some historians believe may have helped trigger the Boudican revolt in Britain. The contrast between his philosophical writings on the worthlessness of wealth and his actual accumulation of substantial personal fortune has been the subject of debate since his own lifetime, when the Roman senator Publius Suillius Rufus publicly attacked him on this point in 58 CE.

Seneca’s response, articulated in his essay On the Happy Life, was that the wise person does not need wealth but is also not required to refuse it when it comes — that what matters is one’s relationship to one’s possessions, not the bare quantity of them. The defence is contested. Some readers find it self-serving. Others find it consistent with the broader Stoic framework, which emphasised the cultivation of an inner attitude rather than the renunciation of external goods. The biographical inconvenience does not, in any case, invalidate the underlying psychological claim. The clinical observation that the pursuit of more does not produce satisfaction can be empirically true even if the person making the observation happens to be wealthy. The Brickman and Easterlin data confirm Seneca’s claim regardless of how the philosopher himself lived.

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For people who carry two copies of the APOE4 gene, the message from clinical medicine over the past three decades has been blunt: your risk of developing Alzheimer’s disease is dramatically elevated, the elevation is genetic, and there is not much you can do about it. About 2 percent of the human population falls into this category. They have inherited one copy of the APOE4 variant from each parent, which combine to produce a 12-fold higher lifetime risk of Alzheimer’s disease compared with people who carry no APOE4 copies. The dogma, until recently, was that this risk was essentially built in. Lifestyle changes might shift the odds at the margins. Nothing was thought to substantially overcome the genetic loading. In August 2025, a research team led by investigators at Mass General Brigham, the Harvard T.H. Chan School of Public Health, and the Broad Institute published a paper in Nature Medicine suggesting that the dogma was wrong — or at least incomplete — and that a specific dietary pattern can substantially modulate even the highest-risk genetic profile.

According to the Mass General Brigham press release accompanying the study, the research team analysed data from approximately 5,700 participants in two long-running US cohorts — the Nurses’ Health Study (4,215 women, followed from 1989 to 2023) and the Health Professionals Follow-up Study (1,490 men, followed from 1993 to 2023). Combined, the data covered more than three decades of dietary records, genetic information, blood metabolomic profiles, and tracking of dementia outcomes across the participants’ lives. The study population was large enough, and the follow-up long enough, to provide statistically meaningful comparisons across genetic-risk subgroups — including the small but critical APOE4 homozygous subgroup, which most previous dietary studies had been too small to analyse on its own.

What the data showed

The headline finding was specific and striking. Per CNN Health’s coverage of the study, participants who most closely followed a Mediterranean dietary pattern — high in vegetables, fruits, nuts, whole grains, legumes, fish, and olive oil; low in red meat, processed meat, and alcohol — showed reduced dementia risk across all genetic-risk categories. The protective effect was modest in people with no APOE4 copies. It was somewhat larger in people with one APOE4 copy. And it was substantially largest in people with two APOE4 copies, in whom close Mediterranean diet adherence was associated with at least a 35 percent reduction in dementia risk compared with APOE4 homozygotes who did not follow the dietary pattern. The protective effect, in other words, scaled with the genetic risk it was working against — the diet helped most in the people who needed it most.

Yuxi Liu, the study’s lead author and a research fellow at Brigham and Women’s Hospital and Harvard Medical School, summarised the finding for CNN: “We followed over 5,700 people for 34 years and found those who followed a baseline Mediterranean diet with little alcohol, red and processed meat but full of vegetables, fruits, nuts, whole grains, legumes, fish and olive oil all reduced the risk of dementia. But the benefit was highest for people with the APOE4 gene, especially those with two copies of APOE4.” Richard Isaacson, an Alzheimer’s specialist not involved in the research, framed the implications more directly: “Hopefully this will change the current dogma that having two copies of the APOE4 is a ‘fait accompli’ for developing Alzheimer’s. Genes do not have to be your destiny.”

The metabolomic mechanism

What distinguishes the 2025 study from earlier dietary research on Alzheimer’s is that the team also measured the participants’ blood metabolomes — the full set of small molecules circulating in their plasma — and tracked how the metabolite profiles varied by genotype and by diet. As documented in the original paper by Yuxi Liu and colleagues in Nature Medicine, the integrated analysis identified 57 specific metabolites whose associations with dementia risk varied by APOE4 genotype or by other Alzheimer’s-related genetic variants. Cholesteryl esters and sphingomyelins, for example, were most strongly associated with increased dementia risk specifically in APOE4 homozygotes. Inverse associations with glycerides — meaning higher glyceride levels were associated with lower dementia risk — were also specific to the APOE4 homozygous genotype.

The Mediterranean diet, in the data, was unusually effective at modulating exactly the metabolites that mattered most in APOE4 homozygotes. The diet pushed cholesteryl ester and sphingomyelin levels downward (reducing dementia-associated metabolites) while supporting glyceride profiles associated with protection. The mechanism is not yet fully characterised, but the integrated metabolomic data provide what the authors call “biological plausibility” for the observed dietary effect — meaning the diet appears to be working through measurable biochemical pathways rather than through some unspecified general health benefit. The combination of long-term outcome data and detailed metabolomic profiling makes the 2025 finding substantially more mechanistically grounded than earlier dietary observational studies that established correlation without identifying the underlying biochemistry.

Why the APOE4 finding matters

The clinical significance of the APOE4 result is hard to overstate. Alzheimer’s disease has a substantial genetic component — heritability has been estimated at up to 80 percent — and APOE is by some distance the strongest single genetic risk factor for the common sporadic form of the disease. The 12-fold elevated risk that comes with carrying two APOE4 copies is among the largest known gene-disease effect sizes in medicine. For decades, the consensus framing was that this genetic load was essentially fixed. Patients who learned through genetic testing that they were APOE4 homozygotes typically received the news as a sentence rather than a probability — something to brace against rather than something to act on.

The 2025 finding does not, by itself, eliminate the elevated risk. A 35 percent reduction in dementia risk among APOE4 homozygotes following a Mediterranean diet still leaves these individuals at substantially elevated risk compared with the general population. What the finding does establish is that the risk is modifiable — that a daily food pattern, sustained over decades, can meaningfully shift the trajectory in a population that previous research had largely written off. As reported in Harvard Health Publishing’s coverage of the study, the practical recommendation for APOE4 carriers is not radically different from what cardiologists and neurologists have been telling everyone for decades — eat more vegetables, more fish, more olive oil, less red meat, less processed food — but the new evidence suggests that for the APOE4 homozygous subgroup specifically, the recommendation may carry substantially more weight than it does for the general population.

Limitations and what comes next

The Liu et al. 2025 paper is an observational study rather than a randomised controlled trial, and the authors acknowledged several limitations that warrant honest framing. The cohort consisted of well-educated individuals of European ancestry, which means the generalisability to other populations — different genetic backgrounds, different food cultures, different socioeconomic contexts — is not yet established. The dietary adherence was self-reported through periodic food-frequency questionnaires rather than objectively measured. The participants who closely followed a Mediterranean diet may have differed from non-followers in unmeasured ways that could partly account for the dementia difference. The 2025 finding is not, on its own, proof that Mediterranean diet directly causes reduced dementia risk in APOE4 homozygotes; it is strong observational evidence consistent with that conclusion.

What the paper adds to the existing literature is the genetic-stratified analysis and the metabolomic mechanism, both of which provide convergent support for the broader claim. Earlier work — the 2023 brain-autopsy study showing 40 percent lower odds of Alzheimer’s pathology in Mediterranean and MIND diet adherents, the FINGER multi-domain lifestyle trial in Finland, the long line of MIND diet research at Rush University — had built the case that diet matters for dementia risk in general populations. The 2025 paper extends the case specifically to APOE4 homozygotes, who had been the most pessimistically counselled subgroup and now appear to be the subgroup with the most to gain from dietary intervention. Whether this translates into changed clinical recommendations, changed genetic-counselling practice, and changed daily behaviour in the 2 percent of the population carrying two APOE4 copies will be the central question for the next several years of Alzheimer’s prevention research. The biological case for the diet has now been made. The cultural case for actually following it is, as always, harder.

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Students who believed in finding their one true passion gave up faster when things got hard. That is the finding, stripped to its bone, of a 2018 paper that has quietly rewired how psychologists talk about career advice.

The researchers — Paul O’Keefe at Yale-NUS College, with Carol Dweck and Gregory Walton at Stanford — proved it with a black hole article. They handed undergraduates an essay that started accessible and turned dense with equations halfway through. The students who treated interests as something you discover — fixed, waiting, predestined — lost interest the moment the physics got hard. The ones who treated interests as something you develop kept reading.

That single experimental setup, published in Psychological Science under the title “Implicit Theories of Interest: Finding Your Passion or Developing It?”, became the empirical spine of a now-common critique: the advice to follow your passion may quietly teach people to quit.

The black hole article that broke the theory

The setup was deliberately simple. Students first identified whether their strongest interests were in the arts and humanities or in math and science. Then they were assigned to read an engaging article outside their stated domain — a STEM student got an essay on Pierre Bourdieu, a humanities student got a piece on black holes.

Almost everyone enjoyed it. The hook worked.

Then came the second article: a dense, technical academic paper on the same topic. This is where the two groups split. Students primed with a fixed theory of interest — the belief that passions are found, not built — reported a sharp drop in fascination. Students primed with a growth theory stayed curious through the hard parts.

The researchers ran the experiment five different ways. The pattern held. People who believed passion was a thing you have treated friction as a signal they had picked the wrong thing.

Why the belief itself is the problem

The mechanism O’Keefe’s team identified is almost philosophical. If you believe your real passion is out there, fully formed, waiting to be recognized, then the first moment something gets boring or painful becomes evidence. Evidence that this wasn’t it. Evidence to move on.

Genuine interest, in that framework, should feel effortless. So effort itself becomes suspicious.

The Yale-NUS and Stanford team called this the cost of a fixed theory of interest. The article on the open-access version of the study is summarized in coverage on the cultural fallout of the follow-your-passion narrative, which sits awkwardly alongside graduation speeches that have been recycling the phrase since the 1980s.

What people quit, and how fast

In one of the O’Keefe experiments, students with a fixed-passion belief predicted, before the study began, that finding their true interest would mean motivation would carry them through anything. They believed friction would be absent because interest would be infinite.

It is hard to imagine a belief better designed to produce disappointment.

When the hard text arrived, their reported interest collapsed by a wide margin compared to the growth-mindset group. They also became less open to interests outside their original identified domain — the fixed view narrows people, the researchers wrote, rather than widens them.

The Forbes coverage of related work points out that passion is typically the reward of sustained effort, not the entry ticket. The order in which people expect to feel passion seems to determine whether they ever feel it.

The ghost of Steve Jobs

The modern version of the advice has a clear origin. Steve Jobs, Stanford commencement, June 2005, told graduates the only way to do great work was to love what they did, and if they hadn’t found it yet, to keep looking. The speech has been widely viewed online.

Cal Newport, the Georgetown computer scientist who wrote So Good They Can’t Ignore You, was among the first to point out that Jobs himself didn’t follow his own advice. Jobs was interested in Zen Buddhism and calligraphy. He built a personal computer company because a friend asked him to help sell circuit boards.

The passion came later. After the work.

Leadership coach Amina AlTai, in a December 2025 interview, told CNBC the advice “positions us to fizzle out fast” because it sets up an expectation of permanent emotional fuel. Real work doesn’t come with permanent emotional fuel. It comes with mortgages and Tuesday afternoons.

What the study did not say

O’Keefe’s team was careful not to argue against having interests, or against pursuing them. The finding was narrower and more specific: the theory people hold about where interests come from changes how they behave when interests stop being fun.

A person who believes interests develop will sit through a confusing equation. A person who believes interests are discovered will close the tab.

The students reading about black holes were not less smart, less curious, or less ambitious than each other. They had been handed different stories about how curiosity is supposed to feel. That alone changed how long they kept reading.

The slow version of passion

The implication that has stuck, almost a decade after the paper, is that passion is more like a long marriage than a first date. It deepens because you stay. It survives the boring stretches because you treat the boring stretches as part of it, not as evidence against it.

The reverse is also true. People who expect first-date energy at year seven leave at year seven.

This is why the 2018 finding keeps getting cited in career-advice columns, leadership books, and the slow drip of essays pushing back on the Jobs commencement speech. The study didn’t just measure quitting. It identified the sentence in someone’s head — this must not be my real passion — that turns a hard Tuesday into a resignation letter.

The article in the textbook

If you go back to the original 2018 paper, the most quietly devastating detail is in the methods section. The hard article the students were asked to read — the one that made the fixed-passion believers lose interest — wasn’t unusually difficult. It was a standard piece of upper-level academic writing. The kind of thing every person who has ever developed a real expertise has had to push through hundreds of times.

The students who believed passion was something you find treated it as a stop sign. The students who believed passion was something you build treated it as a hill.

Same article. Same equations. Different story about what the difficulty meant.

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Most people who are quietly miserable do not know it. That, in essence, is what a Danish philosopher named Søren Kierkegaard tried to tell the readers of nineteenth-century Copenhagen in 1849, and what the empirical psychology of regret has been confirming, in laboratory studies and museum surveys, for the past three decades. When most people use the word “despair,” they mean acute unhappiness — the kind of low mood that follows a loss, a failure, or a difficult life event. Despair in this ordinary sense is something a person is aware of. They can name it, describe it, and (with luck) move through it. Kierkegaard, writing under the pseudonym Anti-Climacus, used the word in a substantially different way. The despair he described was not an emotion. It was a structural condition of the self, present in the great majority of human beings, generally unnoticed by the people who carried it, and most acute precisely in those who did not know they had it. Kierkegaard’s book on the subject, The Sickness Unto Death, is one of the founding texts of existentialist philosophy.

According to the Stanford Encyclopedia of Philosophy’s entry on Kierkegaard, the framework rests on a specific definition of what the self is. For Kierkegaard, the self is not a thing or a substance. It is “a relation that relates itself to itself” — a dynamic process by which a human being takes up the various contradictory features of being human (finite and infinite, possible and necessary, free and determined) and synthesises them into a coherent personality. The self is not given at birth; it is something a person has to become. And despair, in Kierkegaard’s account, is the misrelation that occurs when this becoming fails — when the synthesis goes wrong, when the person fails to take on the self they were capable of being.

The three forms of despair

Kierkegaard identified three primary configurations the failure can take. The first and most common is the despair of ignorance — being in despair without knowing it. A person in this state has not yet noticed any gap between the life they are living and the life they were capable of living. Their attention is consumed by the routine surfaces of daily existence: work, possessions, social position, the consumption of entertainment. The deeper question of what kind of person they are, in any meaningful sense, has never been seriously posed. Kierkegaard considered this unconscious form to be the dominant pattern in modern society — most people, in his view, were in despair without realising it, because the structures of their lives had insulated them from ever asking the question.

The second form is the despair of weakness — knowing what self one is meant to be and not being willing to be it. The person in this state has had some glimpse of their own possibilities and has, for whatever combination of fear, comfort, social pressure, or fatigue, declined to pursue them. The third form is the despair of defiance — willing to be a self other than the one one is, refusing the actual configuration of one’s life in favour of an imaginary or constructed alternative. The defiant form, Kierkegaard thought, was the most acute but also the rarest. As one frequently-cited line from the book puts it: “The greatest hazard of all, losing the self, can occur very quietly in the world, as if it were nothing at all. No other loss can occur so quietly; any other loss — an arm, a leg, five dollars, a wife, etc. — is sure to be noticed.”

What modern psychology has found

Kierkegaard was writing in 1849, in a theological framework, with no empirical methodology beyond his own observation of the people around him in nineteenth-century Copenhagen. His specific claims about despair as a sickness of the spirit cannot be tested in the same way an empirical hypothesis can be tested. What can be tested is whether the basic phenomenon he described — that the failures most haunting to people across a life are the failures to become the self one was capable of being — shows up in modern psychological data on regret. The answer is that it does. Per a 2023 replication in Royal Society Open Science of the foundational research by Thomas Gilovich and Victoria Medvec at Cornell University, the empirical psychology of regret converges on a striking temporal pattern: in the short term, people’s most acute regrets tend to be about things they did and wish they had not done. In the long term, the pattern reverses. The regrets that haunt people across years and decades, and that dominate when people look back on their lives as a whole, are overwhelmingly about things they did not do — chances not taken, paths not pursued, selves not allowed to emerge.

Gilovich and Medvec’s original 1994 paper in the Journal of Personality and Social Psychology found this pattern across multiple population groups, including a sample of nursing-home residents reflecting on their entire lives. The 2023 replication, conducted at a Chicago museum of psychological science with a large public sample, reproduced the temporal interaction even though the specific magnitudes differed. The pattern is now considered one of the more robust findings in the empirical literature on regret. Its philosophical implication aligns closely with Kierkegaard’s framework, even though the researchers involved generally do not cite him.

Why the despair is so quiet

The most disconcerting feature of Kierkegaard’s account is his insistence that this despair is, in its most common form, undetectable to the person carrying it. Unlike acute sadness, which announces itself, the unconscious form of despair tends to be hidden by the very busyness of life that produces it. A person fully occupied with work, family obligations, consumption of news and entertainment, social media, the small daily tasks of contemporary existence, is unlikely to encounter the question of whether they are actually becoming the self they were meant to be. The question requires solitude, reflection, and a degree of confrontation with one’s own choices that ordinary life does not generally provide. As reported in D. Anthony Storm’s commentary on The Sickness Unto Death, Kierkegaard described despair as a “misrelation in the relation of a synthesis that relates itself to itself” — a sickness that, unlike most diseases, the patient is largely responsible for and from which the patient cannot escape simply by avoiding awareness of it. The avoidance, in Kierkegaard’s framework, is itself part of the despair.

What the framework does not promise

Intellectual honesty requires noting what Kierkegaard’s account does not establish. It is not a recipe for happiness. It does not specify what self any given person was meant to become, or how to identify that self, or how to pursue it once identified. Kierkegaard’s own answer to the question of how despair is overcome was specifically Christian — through a particular relation to God that he called faith — and many modern readers find that the theological framing limits the framework’s applicability. The diagnostic side of his work, however, has had broad influence well beyond the specifically Christian context, including on the existentialist philosophers of the twentieth century, on the founders of existential psychotherapy, on Erik Erikson’s developmental concept of “integrity versus despair” in late life, and on the broader twentieth-century literature on authenticity and self-realisation. What the framework provides is a vocabulary for naming a condition that often goes unnamed — the slow recognition, late in a life, that the person one has been is not quite the person one started out hoping to be. Kierkegaard called this the breaking through of despair into consciousness, and he thought it was, paradoxically, a kind of progress. The unconscious form, in his account, was worse than the conscious form, because it left no opening for change.

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