The Wise Old Age of… 35? New Study Suggests Brain Power Peaks Early

The mind at midlife

The Wise Old Age of… 35? New Study Suggests Brain Power Peaks Early

Ask those who’ve entered the thick of middle age what they think about their mental capacities and you’re ly to hear a slew of complaints — their brains don’t work as quickly as they used to, they’re distractable and unfocused, and they can never remember anyone’s name.

While some of these complaints reflect real declines in brain function in our middle years, the deficiencies of a middle-aged brain have ly been overstated by anecdotal evidence and even by some scientific studies.

Contrary to its reputation as a slower, duller version of a youthful brain, it seems that the middle-aged mind not only maintains many of the abilities of youth but actually acquires some new ones.

The adult brain seems to be capable of rewiring itself well into middle age, incorporating decades of experiences and behaviors. Research suggests, for example, the middle-aged mind is calmer, less neurotic and better able to sort through social situations.

Some middle-agers even have improved cognitive abilities.

“There is an enduring potential for plasticity, reorganization and preservation of capacities,” says cognitive neuroscientist Patricia Reuter-Lorenz, PhD, of the University of Michigan in Ann Arbor.

Researchers now have an unprecedented wealth of data on the aging brain from the Seattle Longitudinal Study, which has tracked the cognitive abilities of thousands of adults over the past 50 years.

These results show that middle-aged adults perform better on four six cognitive tests than those same individuals did as young adults, says study leader Sherry Willis, PhD, of the University of Washington in Seattle.

While memorization skills and perceptual speed both start to decline in young adulthood, verbal abilities, spatial reasoning, simple math abilities and abstract reasoning skills all improve in middle age.

Cognitive skills in the aging brain have also been studied extensively in pilots and air-traffic controllers. Again, older pilots show declines in processing speed and memory capacity, but their overall performance seems to remain intact.

In a study published in Neurology (Vol. 68, No. 9) in 2007, researchers tested pilots age 40 to 69 as they performed on flight simulators.

Older pilots took longer to learn to use the simulators but did a better job than their younger colleagues at achieving their objective: avoiding collisions.

Many middle-aged people are convinced that they’re just not as mentally skilled or even as intelligent as they used to be, Willis says. But it’s possible that’s an illusion arising from the aspects of cognition that do suffer in middle age.

“They may get the sense they’re cognitively slow just because they’re perceptually slow or slow with psychomotor skills,” she says, when in reality their brains are performing most tasks remarkably well.

Changing strategies

Researchers used to believe that brain activity would slow down with aging so that older brains would show less activity overall than younger ones. But functional neuroimaging studies have overturned that assumption.

For example, psychologist Cheryl Grady, PhD, of the University of Toronto, and her colleagues have found that older adults use more of their brains than young adults to accomplish certain tasks. In a study published in the Journal of Neuroscience (Vol.

3, No. 2) in 1994, Grady reported that performing a face-matching task activates mainly the occipital visual areas in younger adults, but older adults use these areas as well as the prefrontal cortex. (Both groups of adults are equally skilled at the task.


Several groups, including Grady’s, have also found that older adults tend to use both brain hemispheres for tasks that only activate one hemisphere in younger adults. Younger adults show similar bilateralization of brain activity if the task is difficult enough, Reuter-Lorenz says, but older adults use both hemispheres at lower levels of difficulty.

The strategy seems to work. According to work published in Neuroimage (Vol. 17, No. 3) in 2002, the best-performing older adults are the most ly to show this bilateralization. Older adults who continue to use only one hemisphere don’t perform as well.

Reuter-Lorenz finds these changes with age encouraging, as they show that the middle-aged brain is capable of altering how it does things in order to accomplish the task at hand. “Compensation through some brain mechanisms may make up for losses in others,” she says.

Grady cautions that many studies on the middle-aged brain are preliminary, as this age group “hasn’t been studied very much. It certainly hasn’t been studied enough.

” Most functional imaging studies, for example, tend to recruit college students and retirees as study subjects, Grady says.

Cognitive characteristics of in-between ages are often simply extrapolated from the two ends of the spectrum.

While a linear continuum may be accurate for many traits, it may not always be a valid assumption. Grady’s own work on brain activation during memory tasks, for example, suggests that the middle-aged pattern does fall between those of a young adult and an elderly person.

For example, the amount of white matter in the brain, which forms the connections among nerve cells, seems to increase until age 40 or 50 and then falls off again. “So that suggests that there are some developmental changes that really don’t hit their peak until somewhere in middle age,” Grady says.

At least the glasses are rose-colored

Emotions and social interactions — even personality — may systematically change as people enter middle age. Many studies have found that people become calmer and less neurotic as they age. “There’s a quieting of emotional storms,” Reuter-Lorenz says.

Work by cognitive psychologist Mara Mather, PhD, of the University of Southern California in Los Angeles, has found that older adults tend to focus more on positive information and less on negative information than their younger counterparts.

In 2004, she and her colleagues reported in Psychological Science (Vol. 15, No. 4) that the amygdala in older adults actually responds less to negative stimuli (such as unpleasant pictures) than it does in young adults.

Starting around age 40, people also show a better memory for positive images than for negative ones, and this trend continues until at least age 80.

This “positivity effect” is seen even more strongly in people who are doing exceptionally well cognitively, Mather says, “so it doesn’t seem to be something that just goes along with cognitive decline; it seems to be something that’s an active process.”

These findings fit with many self-reports from middle-aged and older individuals, Mather says. Older adults rank emotional stability and positive affect as more important than younger adults do, and they say that they’re better at regulating their own emotions than they were in their youth.

Although scientifically analyzing such qualities as judgment and wisdom is considerably more difficult than measuring psychomotor speed or memory storage capacity, some researchers are trying to do just that.

Research over the past several years has reported that middle-aged people are much more expert at many social interactions — such as judging the true intentions of other human beings — than are those either younger or older.

And work by David Laibson, PhD, at Harvard University, found that adults in midlife show better economic understanding and make better financial decisions than either younger or older adults. In fact, the average person’s financial judgment seems to peak at 53.

Variability and influences

One of the middle-aged mind’s most striking features may not be any one feature or ability, but rather the variation in cognitive skills that’s found in this age group. Although differences in cognition obviously exist among individuals at all ages, these differences seem to increase in middle age.

For example, memory and attention frequently suffer in middle age, but some individuals’ abilities actually improve in midlife. In Willis’s Seattle study, most participants’ ability to remember lists of words declined in middle age, but about 15 percent performed better on this task than they did as young adults.

“If you study a wide range of abilities, you begin to realize how very complex cognitive decline is and how many individual differences there are,” Willis says.

This variation in behavioral performance is also reflected in expression of genes related to learning and memory. In a study published in Nature in 2004 (Vol. 429, No.

6,994), the brains of adults under age 40 consistently showed little damage and high levels of expression of these genes, while brains from those over 73 showed lots of damage and low gene expression. But in the middle-aged group, results varied widely.

Some middle-aged brains were already shutting down, whereas others were indistinguishable from a 30-year-old brain.

“It’s a very interesting and heterogeneous group,” Grady says.

With more study of middle age in general — especially of those who seem to glide through those years with cognitive abilities intact or even improving — scientists hope to enable many more people to preserve cognitive health into old age.

So far, research suggests that remaining cognitively impressive with age comes from adopting certain behaviors as well as possessing some genetic luck, Willis says.

For example, researchers have identified several gene variants that are risk factors for early memory problems.

But people who show cognitive improvement in midlife also tend to be more physically, cognitively and socially active than those who don’t fare as well.

“Instead of a crisis, middle age should be thought of as a time for a new form of self-investment,” Reuter-Lorenz says. “This time of life brings so many new opportunities to invest in your own cognitive and physical resources, so you can buffer against the effects of older age.”

Melissa Lee Phillips is a writer in Seattle.


Brain-age in midlife is associated with accelerated biological aging and cognitive decline in a longitudinal birth cohort

The Wise Old Age of… 35? New Study Suggests Brain Power Peaks Early

Brain-age in midlife is associated with accelerated biological aging and cognitive decline in a longitudinal birth cohort

  • Neuroscience
  • Predictive markers

An individual’s brainAGE is the difference between chronological age and age predicted from machine-learning models of brain-imaging data.

BrainAGE has been proposed as a biomarker of age-related deterioration of the brain. Having an older brainAGE has been linked to Alzheimer’s, dementia, and mortality. However, these findings are largely cross-sectional associations which can confuse age differences with cohort differences.

To illuminate the validity of brainAGE as a biomarker of accelerated brain aging, a study is needed of a large cohort all born in the same year who nevertheless vary on brainAGE.

In the Dunedin Study, a population-representative 1972–73 birth cohort, we measured brainAGE at age 45 years, as well as the pace of biological aging and cognitive decline in longitudinal data from childhood to midlife (N = 869). In this cohort, all chronological age 45 years, brainAGE was measured reliably (ICC = 0.81) and ranged from 24 to 72 years.

Those with older midlife brainAGEs tended to have poorer cognitive function in both adulthood and childhood, as well as impaired brain health at age 3. Furthermore, those with older brainAGEs had an accelerated pace of biological aging, older facial appearance, and early signs of cognitive decline from childhood to midlife.

These findings help to validate brainAGE as a potential surrogate biomarker for midlife intervention studies that seek to measure dementia-prevention efforts in midlife. However, the findings also caution against the assumption that brainAGE scores represent only age-related deterioration of the brain as they may also index central nervous system variation present since childhood.

While old age is associated with higher risk for disease across the entire body, degeneration of the brain and consequent cognitive decline has an outsized influence on disability and loss of independence in older adults [1]. As such there is growing need for interventions to slow the progression of cognitive decline.

Unfortunately, to date, tested interventions have not slowed age-related cognitive decline [2]. The failure of these interventions may be related to their targeting of individuals too late in the aging process after neurodegeneration has become inexorable [3, 4].

Alzheimer’s disease and related dementias (ADRD) arise at the end of a chronic pathophysiological process with preclinical stages emerging decades earlier in life [3].

Evaluating interventions to prevent ADRD onset requires the identification of surrogate biomarkers that index subclinical cognitive decline, neurodegeneration, and accelerated aging of the brain by midlife.

While everyone ages chronologically at the same rate, this is not true biologically; some individuals experience accelerated age-related biological degeneration [5, 6].

For decades, researchers have worked to quantify the rate of biological aging and better understand the mechanisms that generate individual differences in the aging process [7].

The resulting measures of accelerated biological aging have been associated with health span, cognitive decline, cancer risk, and all-cause mortality [5, 6, 8]. However, such aging biomarkers have not directly quantified aging in the organ most directly linked to ADRD, namely the brain.

To address this gap, a recently developed measure called “brain-age” has been proposed as a biomarker for accelerated aging of the brain [9, 10]. Brain-age is a relatively novel measure derived from neuroimaging, but its interpretation is uncertain.

Brain-age is estimated by training machine-learning algorithms to predict age from structural magnetic resonance imaging (MRI) data collected in large samples of individuals across a broad age range [11].

These machine-learning algorithms “learn” multivariate patterns from MRI data that are useful in explaining variance in chronological age across individuals.

The difference between an individual’s predicted age MRI data and their chronological age is called the brain age gap estimate (brainAGE) and is usually interpreted as a measure of accelerated aging of the brain. Older brainAGE has been associated with mild cognitive impairment, ADRD, and mortality [11, 12].

Individuals with an older brainAGE are more ly to have risk factors for dementia including obesity, diabetes, alcoholism, and traumatic brain injury [9, 12,13,14]. Initial studies suggest that brainAGE may be able to predict cognitive decline and conversion to ADRD in older adults in their 60s, 70s, and 80s [15, 16].

But there is no evidence linking brainAGE to earlier signs of cognitive decline or accelerated aging in midlife, the age when surrogate biomarkers may be more effectively used in ADRD-prevention efforts [4]. Promising results notwithstanding, research on brainAGE is still in its infancy.

Reported associations between brainAGE and risk factors for accelerated aging are largely cross-sectional. Inferring within-subject decline and aging from cross-sectional associations in people of different-age cohorts has many pitfalls and is prone to confuse aging with cohort differences (e.g.

, Intelligence Quotient (IQ) scores are higher in members of more recent cohorts, and there are marked generational differences in exposure to diseases, toxins, antibiotics, education, and nutrition which can influence brain measures, including neuroimaging data) [17,18,19]. Cross-sectional observations that older brainAGE is associated with ADRD and many of its risk factors are consistent with at least two perspectives on brain aging, each of which has distinct implications.

The first perspective is that older brainAGE could be an indicator of accelerated brain aging that has accumulated over an individual’s lifetime and increases susceptibility to ADRD and age-related cognitive decline. This perspective implies that at some point in early development, all individuals have a brainAGE that is very close to zero.

BrainAGE scores then diverge with time from chronological age, as genetic, environmental, and lifestyle factors create variation in the rate of brain aging. Here we will refer to this perspective broadly as the “geroscience perspective” [20].

This perspective is the geroscience hypothesis which states that aging is the result of deterioration across multiple organ systems and that furthermore this deterioration is the root cause of age-related disease. It is hypothesized that treatments that can slow this decline will therefore reduce the risk for age-related disease.

This theoretical interpretation of brainAGE is the dominant interpretive framework found in the brainAGE literature [10, 11, 21].

The second perspective on brain aging is the “early system-integrity” perspective of cognitive/biological aging [22]. According to this perspective, individuals vary in their brain and body health from the beginning of life.

Moreover, according to the system-integrity view, the correlation between brain and body health persists across the lifespan so that both brain and body health predict aging outcomes [23,24,25].

From this perspective, the reason brainAGE predicts ADRD and mortality later in life is because brainAGE is an indicator of compromised lifelong brain health [26, 27].

Instead of reflecting accelerated brain aging and the brain’s accumulated biological degeneration, an older brainAGE at midlife reflects compromised system integrity that has been present since childhood and stable for decades. Importantly these two perspectives are not mutually exclusive and both may help explain the phenomenon of accelerated brain aging.

Here we tested to what extent older brainAGE is associated with accelerated aging and to what extent older brainAGE reflects stable individual differences in system integrity in the Dunedin Study.

First, we hypothesized that if individuals with an older brainAGE have brains that are aging faster, they should also have a body that has aged faster, given that, according to the geroscience perspective, aging is the progressive, generalized deterioration, and loss-of-function across multiple organ systems [28, 29]. Second, we hypothesized that if individuals with older brainAGE have undergone accelerated aging they should show signs of cognitive decline [30]. Third, if older midlife brainAGE represents system integrity from early life, we hypothesized that older brainAGE should be correlated with poorer neurocognitive functioning as assessed already in early childhood.

See Supplementary Information for expanded “Methods” section.


Participants are members of the Dunedin Longitudinal Study, a representative birth cohort (N = 1037; 91% of eligible births; 52% male) born between April 1972 and March 1973 in Dunedin, New Zealand (NZ), who were eligible residence in the province and who participated in the first assessment at age 3 years [31].

The cohort represented the full range of socioeconomic status in the general population of NZ’s South Island and as adults matches the NZ National Health and Nutrition Survey on key adult health indicators (e.g.

, body mass index (BMI), smoking, and GP visits) and the NZ Census of citizens of the same age on educational attainment. The cohort is primarily white (93%), which matches the demographics of the South Island.

Assessments were carried out at birth and ages 3, 5, 7, 9, 11, 13, 15, 18, 21, 26, 32, 38, and most recently (completed April 2019) 45 years, when 94% (N = 938) of the 997 participants still alive took part. Each participant was brought to the research unit for 1.5 days of interviews and examinations.

Written informed consent was obtained from participants and study protocols were approved by the NZ Health and Disability Ethics Committee. Brain imaging was carried out at age 45 years for 875 study members (93% of age-45 participants).

Data from six study members were excluded due to major incidental findings or previous head injuries (e.g., large tumors or extensive damage to the brain). This resulted in brain-imaging data for our current analyses from 869 study members, who represented the original cohort (attrition analysis in Supplementary; Supplementary Figs. S1 and S2).

MRI acquisition

Study participants were scanned using a Siemens Skyra 3T scanner (Siemens Healthcare, Erlangen, Germany) equipped with a 64-channel head/neck coil at the Pacific Radiology imaging center in Dunedin, New Zealand.

High resolution structural images were obtained using a T1-weighted MP-RAGE sequence with the following parameters: TR = 2400 ms; TE = 1.98 ms; 208 sagittal slices; flip angle, 9°; FOV, 224 mm; matrix = 256 × 256; slice thickness = 0.9 mm with no gap (voxel size 0.9 × 0.

875 × 0.875 mm); and total scan time = 6 min and 52 s.


We generated brainAGE scores using a recently published, publicly available algorithm [13]. This method uses a stacked algorithm to predict chronological age from multiple measures of brain structure derived from Freesurfer version 5.3 [32].

Specifically, the algorithm is trained on vertex-wise cortical thickness and surface area data extracted from fsaverage4 standard space as well as subcortical volume extracted from the aseg parcellation. Test–retest reliability was assessed in 20 Dunedin Study members (mean interval between scans = 79 days).

The ICC of brainAGE was 0.81 (95% CI = 0.59–0.92; p


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