Why Is My Memory Getting Worse? What BDNF and Klotho Have to Do With It

You pick up your phone to check the time, then put it down having done absolutely everything except check the time. You go completely blank on a word you are a hundred percent sure you know. You read the same page twice and it still did not really land.

These are not just bad days or too much coffee. They often reflect a genuine biological shift, specifically in two proteins that neuroscientists have become increasingly excited about: BDNF and Klotho. Both decline with age. Both track closely with how sharp you stay. And both respond to how you live in ways that are surprisingly well-documented for a field that often overpromises.

What Is BDNF?

Brain-Derived Neurotrophic Factor is a protein that supports the survival and growth of neurons, and helps reinforce the connections between them. Researchers sometimes call it "brain fertiliser," which is the kind of metaphor that slightly oversells things but is not entirely wrong.

The mechanism that matters most for memory is called long-term potentiation: every time a signal travels along a neural pathway, BDNF helps make that route a little stronger and easier to use again. Less BDNF means weaker pathways, slower recall, and that specific frustration of knowing a word exists but being completely unable to locate it (1, 3).

BDNF is most concentrated in the hippocampus (memory formation) and the prefrontal cortex (focused thinking and decision-making) (2). It also regulates serotonin, dopamine, and glutamate, which partly explains why mood and cognitive sharpness tend to decline together rather than independently. Clinically, low BDNF levels show up consistently in major depressive disorder, bipolar disorder, and Alzheimer's disease. Many antidepressants appear to work partly by raising BDNF, which has made it a serious target for psychiatric research (4, 5).

We have a full article on What Is BDNF? if you want to go deeper.

What Is Klotho?

The protein is named after Klotho, the Greek goddess who spins the thread of life, a name that turns out to reflect its biology more closely than most.

The initial animal evidence was unambiguous: mice lacking the Klotho gene age catastrophically fast: organ failure, bone deterioration, cognitive collapse, all within weeks. Give a different set of mice extra Klotho and they live up to 30% longer, staying cognitively sharper throughout (6). That is an animal study and you are not a mouse, but it established the protein's significance clearly enough that serious human research followed.

In people, Klotho circulates in the blood and cerebrospinal fluid, produced mainly by the kidneys and the brain. Its job description is broad: protecting neurons from oxidative damage, dampening chronic inflammation, maintaining the myelin sheath around nerve fibres, and supporting the receptors involved in memory consolidation (7, 8, 9).

The less cheerful part: Klotho levels fall steadily with age, and lower levels are consistently associated with faster cognitive decline, higher cardiovascular risk, and increased all-cause mortality (7, 8). It is not a perfect predictor of anything, but as biological signals go, it is a fairly informative one.

How BDNF and Klotho Are Connected

They are not simply two proteins that both happen to be good for you. A 2025 study published in BMC Psychiatry measured Klotho, BDNF, and two other neurotrophic factors in 48 male patients with bipolar disorder alongside 48 healthy controls, then tested cognitive performance using the Stroop test (10).

Klotho independently predicted performance on the most demanding cognitive tasks. BDNF was associated with processing speed. And both appeared to function as part of a shared neuroplasticity network rather than acting in isolation, a pattern that has now emerged across studies in bipolar disorder, schizophrenia, and other conditions where cognition is impaired (10).

To be clear about the limitations: the study was male-only, sample sizes were modest, and Klotho was measured in serum rather than cerebrospinal fluid. Larger and more diverse trials are still needed. But the pattern is consistent with what other research has been pointing toward for some time.

What the Broader Evidence Shows

Higher BDNF consistently tracks with better memory, verbal learning, and executive function across human studies. A systematic review and meta-analysis confirmed it behaves almost like a real-time readout of brain state in bipolar disorder, falling during episodes and recovering during remission (5). That kind of responsiveness is biologically significant. It means BDNF is not purely fixed by genetics or age.

For Klotho, an analysis of 2,171 US adults aged 60 to 79 found that those with the highest circulating levels performed significantly better across multiple cognitive tests (11). A gene variant called KL-VS, which causes naturally elevated Klotho production, is associated with better cognitive aging and lower Alzheimer's risk, including in people who carry the APOE4 risk gene (9, 12). That is the kind of finding that attracts attention.

In 2023, a single low-dose Klotho injection given to aged rhesus macaques improved memory within hours (13). A Phase 1 human trial is now underway at UCSF. The sample sizes are small and macaque results do not always transfer to humans, but the direction of evidence has been consistent enough that serious funding has followed.

What Actually Affects Your Levels

Exercise. Yes, again. We know.

It is exercise. If you were hoping this section would be different, we are sorry. The reason it keeps appearing is not that researchers lack imagination. It is that the evidence is so consistently strong, across so many different outcomes, that omitting it would be doing you a genuine disservice.

For BDNF and Klotho specifically, the effect is unusually direct. A randomised controlled trial found that both moderate aerobic exercise and HIIT significantly raised plasma Klotho over 12 weeks in sedentary middle-aged adults (14). For BDNF, even a single session of aerobic exercise produces an acute spike, and sustained training raises the baseline over time (1, 6). If there is one recommendation in this article worth acting on, this is it, not because it is easy to say but because the evidence supports it above everything else.

We compared HIIT versus Zone 2 training for longevity outcomes if you want help deciding which is worth more of your time.

Diet

High flavonoid intake from berries, dark chocolate, and green tea is linked to measurable BDNF increases and cognitive improvements in two randomised controlled trials (16). That is genuinely good news, and not just because dark chocolate is involved. Omega-3 supplementation raised serum BDNF and reduced depression severity in a 2025 double-blind clinical trial (17). For Klotho, a nutrient-dense diet and healthy body weight consistently predict higher levels, while excess adiposity tends to suppress them (7, 8).

More on the specifics in our articles on omega-3s and brain aging and optimal longevity nutrition.

Intermittent Fasting

Intermittent fasting raises BDNF in animal models through cellular stress-response pathways, with early human data pointing in the same direction (18). The evidence is less robust than for exercise or diet, so treat it as promising rather than established. Our autophagy and longevity article covers the cellular mechanics for the curious.

Sleep and Stress

Chronic sleep deprivation suppresses BDNF. Chronic stress elevates cortisol, which drives neuroinflammation and actively depresses BDNF production. Neither finding is surprising, but it is worth stating plainly: the cognitive fog that brought you here is not only shaped by what you do during waking hours. A significant portion of the repair work happens at night, and it requires the right conditions. Seven to nine hours of quality sleep and a practical approach to managing stress are part of the biological picture, not soft lifestyle advice appended at the end to round out an article. We have a practical guide to coping with daily stress if that is the area most in need of attention.

Conclusion

BDNF and Klotho decline with age. Both track closely with memory, processing speed, and cognitive resilience. And both respond to factors that are, for the most part, modifiable.

The most robust evidence points to aerobic exercise as the primary lever, with diet quality, sleep, and stress management playing supporting roles. Certain supplements, including omega-3 fatty acids and curcumin, have randomised trial data supporting their effect on BDNF (17, 19) and may be worth considering alongside a solid lifestyle foundation. Augment Life formulates both to research-aligned standards.

Cognitive aging is not a fixed trajectory. The biology covered here suggests it is, to a meaningful degree, a process you can influence.

Read More From Augment Life

• What Is BDNF?
• The Impact of Omega-3 Fatty Acids on Brain Aging
• What Is an Optimal Longevity Diet?
• Do HIIT and Zone 2 Workouts Influence Longevity?
• The Role of Autophagy in Health and Longevity
• How Can We Cope With the Stress of Daily Life?

Literature Sources

1. Bathina S, Das UN. Brain-derived neurotrophic factor and its clinical implications. Arch Med Sci. 2015. doi: 10.5114/aoms.2015.56342
2. Li S, Weinstein G, Zare H, et al. The genetics of circulating BDNF. Brain Commun. 2020. doi: 10.1093/braincomms/fcaa176
3. Mora E, Portella MJ, Pinol-Ripoll G, et al. High BDNF serum levels and cognitive functioning in bipolar disorder. Eur Psychiatry. 2019. doi: 10.1016/j.eurpsy.2019.02.006
4. Carniel BP, da Rocha NS. BDNF and inflammatory markers in depression. Prog Neuropsychopharmacol Biol Psychiatry. 2021. doi: 10.1016/j.pnpbp.2020.110151
5. Fernandes BS et al. BDNF as a state marker of mood episodes. J Psychiatr Res. 2011. doi: 10.1016/j.jpsychires.2011.03.002
6. Kurosu H et al. Suppression of aging in mice by the hormone klotho. Science. 2005. doi: 10.1126/science.1112766
7. Donate-Correa J et al. Pathobiology of the Klotho antiaging protein. Front Aging. 2022. doi: 10.3389/fragi.2022.931331
8. Deng L et al. Serum klotho and cognitive performance in US adults. Front Aging Neurosci. 2023. doi: 10.3389/fnagi.2023.1053390
9. Dubal DB et al. Klotho enhances cognition in mouse models. J Neurosci. 2015. doi: 10.1523/JNEUROSCI.5791-12.2015
10. Celebi Z et al. Klotho, neurotrophic factors and cognition in bipolar disorder. BMC Psychiatry. 2025. doi: 10.1186/s12888-025-06469-0
11. Deng L et al. Serum klotho and cognitive performance in US adults. Front Aging Neurosci. 2023. doi: 10.3389/fnagi.2023.1053390
12. Belloy ME et al. Klotho-VS heterozygosity and Alzheimer risk. JAMA Neurol. 2020. doi: 10.1001/jamaneurol.2020.0414
13. Castner SA et al. Longevity factor klotho enhances cognition in primates. Nat Aging. 2023. doi: 10.1038/s43587-023-00441-x
14. Amaro-Gahete FJ et al. Exercise training increases plasma Klotho. J Sports Sci. 2019. doi: 10.1080/02640414.2019.1626048
15. Pappolla A et al. Klotho as an emerging exerkine. Sci Rep. 2022. doi: 10.1038/s41598-022-22123-1
16. Neshatdoust S et al. Flavonoids and BDNF cognitive improvements. Nutr Healthy Aging. 2016. doi: 10.3233/NHA-1615
17. Gholipour D et al. Omega-3 supplementation increases BDNF. J Hum Nutr Diet. 2025. doi: 10.1111/jhn.70076
18. Alkurd R et al. Intermittent fasting and BDNF levels. Medicina. 2024. doi: 10.3390/medicina60010191
19. Sarraf P et al. Curcumin supplementation and serum BDNF. Nutr Res. 2019. doi: 10.1016/j.nutres.2019.05.001