# Dietary Bioactives and Physical Activity in the Regulation of Hippocampal Neurogenesis and Cognitive Decline

**Authors:** Zhenyi Zhao, Sima‐sadat Sabihi

PMC · DOI: 10.1002/fsn3.71613 · Food Science & Nutrition · 2026-03-09

## TL;DR

This paper reviews how diet and exercise together can improve brain health and reduce cognitive decline by boosting hippocampal function.

## Contribution

It highlights the synergistic effects of dietary bioactives and physical activity on hippocampal neurogenesis and neuroinflammation.

## Key findings

- Dietary bioactives and exercise work together to enhance hippocampal plasticity and cognitive function.
- Key pathways include BDNF signaling, inflammation control, and mitochondrial regulation.
- Lifestyle-based strategies show promise for maintaining brain health in aging and neurodegenerative conditions.

## Abstract

Aging and neurodegenerative disorders are distinguished by dysfunction within the hippocampus, resulting in compromised spatial memory and cognitive deterioration. The modulation of neurogenesis and neuroinflammation has surfaced as a promising strategy to restore hippocampal functionality and enhance cognitive capabilities. Natural substances, encompassing polyphenols, flavonoids, and various bioactive compounds, display neuroprotective, antioxidant, and anti‐inflammatory effects, whereas physical exercise promotes neurogenesis, synaptic plasticity, and anti‐inflammatory pathways. Recent findings indicate that the integration of dietary modifications alongside regular physical activity yields synergistic advantages for preserving cerebral health and alleviating cognitive decline. This review consolidates existing knowledge regarding the molecular mechanisms by which natural substances and physical activity impact hippocampal neurogenesis and neuroinflammation. It emphasizes critical pathways, including the regulation of neurotrophic factors, reduction of oxidative stress, and modulation of inflammatory cytokines, which collectively underpin cognitive functionality. Through the amalgamation of nutritional and lifestyle interventions, this methodology presents prospective preventive and therapeutic advantages for geriatric demographics and individuals afflicted with neurodegenerative conditions. Comprehending the intricate relationship between dietary habits and physical activity in relation to cerebral health may facilitate the formulation of accessible, non‐pharmacological strategies aimed at augmenting hippocampal functionality, safeguarding memory retention, and enhancing overall cognitive efficacy.

Exercise and dietary polyphenols enhance hippocampal plasticity and cognitive function via complementary molecular mechanisms. Central pathways include BDNF signaling, inflammation control, and mitochondrial regulation. Although synergy is mainly supported by preclinical data, lifestyle‐based strategies show promise for brain health maintenance.

## Full-text entities

- **Genes:** Sirt3 (sirtuin 3) [NCBI Gene 293615], Gfap (glial fibrillary acidic protein) [NCBI Gene 24387], Ppargc1a (PPARG coactivator 1 alpha) [NCBI Gene 83516] {aka LRPGC1, PGC-1v, PGCvf, PGCvf-1, PGCvf1, Ppargc1}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, Sirt1 (sirtuin 1) [NCBI Gene 309757] {aka Sir2}, Hes1 (hes family bHLH transcription factor 1) [NCBI Gene 29577], Pik3cb (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit beta) [NCBI Gene 85243], Notch1 (notch receptor 1) [NCBI Gene 25496] {aka NOTCH, TAN1}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, Mapk8 (mitogen-activated protein kinase 8) [NCBI Gene 116554] {aka JNK}, PRKN (parkin RBR E3 ubiquitin protein ligase) [NCBI Gene 5071] {aka AR-JP, LPRS2, PARK2, PDJ}, Bax (BCL2-associated X protein) [NCBI Gene 12028], Sod2 (superoxide dismutase 2) [NCBI Gene 24787] {aka MnSOD}, Rps6kb1 (ribosomal protein S6 kinase B1) [NCBI Gene 83840] {aka p70 S6K-alpha}, Ephb1 (Eph receptor B1) [NCBI Gene 24338] {aka Ephb2, Erk, elk}, Tnf (tumor necrosis factor) [NCBI Gene 24835] {aka RATTNF, TNF-alpha, Tnfa}, Cat (catalase) [NCBI Gene 24248] {aka CS1, Cas1, Cat01, Catl, Cs-1}, Ache (acetylcholinesterase) [NCBI Gene 83817], Maoa (monoamine oxidase A) [NCBI Gene 29253] {aka Mao}, PINK1 (PTEN induced kinase 1) [NCBI Gene 65018] {aka BRPK, PARK6}, DCX (doublecortin) [NCBI Gene 1641] {aka DBCN, DC, LISX, SCLH, XLIS}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, Wnt3 (Wnt family member 3) [NCBI Gene 24882] {aka INT4}, PRKAB1 (protein kinase AMP-activated non-catalytic subunit beta 1) [NCBI Gene 5564] {aka AMPK, HAMPKb}, Mtor (mechanistic target of rapamycin kinase) [NCBI Gene 56718] {aka Frap1, RAFT1}, BDNF (brain derived neurotrophic factor) [NCBI Gene 627] {aka ANON2, BULN2}, Hes5 (hes family bHLH transcription factor 5) [NCBI Gene 79225], NTRK2 (neurotrophic receptor tyrosine kinase 2) [NCBI Gene 4915] {aka DEE58, EIEE58, GP145-TrkB, OBHD, TRKB, trk-B}, Il6 (interleukin 6) [NCBI Gene 24498] {aka ILg6, Ifnb2}, Nrg1 (neuregulin 1) [NCBI Gene 112400], Pik3r1 (phosphoinositide-3-kinase regulatory subunit 1) [NCBI Gene 18708] {aka PI3K, p50alpha, p55alpha, p85alpha}, NR3C1 (nuclear receptor subfamily 3 group C member 1) [NCBI Gene 2908] {aka GCCR, GCR, GCRST, GR, GRL}, VEGFA (vascular endothelial growth factor A) [NCBI Gene 7422] {aka L-VEGF, MVCD1, VEGF, VPF}, SIRT1 (sirtuin 1) [NCBI Gene 23411] {aka SIR2, SIR2L1, SIR2alpha}, Gsk3b (glycogen synthase kinase 3 beta) [NCBI Gene 84027], Bdnf (brain-derived neurotrophic factor) [NCBI Gene 24225], Becn1 (beclin 1) [NCBI Gene 114558] {aka Beclin1}, Ctnnb1 (catenin beta 1) [NCBI Gene 84353] {aka Catnb}, Dcx (doublecortin) [NCBI Gene 84394], Bdnf (brain derived neurotrophic factor) [NCBI Gene 12064], MAPK1 (mitogen-activated protein kinase 1) [NCBI Gene 5594] {aka ERK, ERK-2, ERK2, ERT1, MAPK2, NS13}, Lin28a (lin-28 homolog A) [NCBI Gene 83557] {aka Gm10299, Lin-28, Lin28, Tex17, lin-28A}, CTSB (cathepsin B) [NCBI Gene 1508] {aka APPS, CPSB, KWE, RECEUP}, IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, MTOR (mechanistic target of rapamycin kinase) [NCBI Gene 2475] {aka FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS}, Akt1 (AKT serine/threonine kinase 1) [NCBI Gene 24185] {aka Akt}, Creb1 (cAMP responsive element binding protein 1) [NCBI Gene 81646] {aka Creb}, Vegfa (vascular endothelial growth factor A) [NCBI Gene 83785] {aka VEGF-A, VEGF111, VEGF164, VPF, Vegf}, NTF3 (neurotrophin 3) [NCBI Gene 4908] {aka HDNF, NGF-2, NGF2, NT-3, NT3}, NFE2L2 (NFE2 like bZIP transcription factor 2) [NCBI Gene 4780] {aka IMDDHH, NRF2, Nrf-2}, CTNNB1 (catenin beta 1) [NCBI Gene 1499] {aka CTNNB, EVR7, MRD19, NEDSDV, armadillo}, NR3C2 (nuclear receptor subfamily 3 group C member 2) [NCBI Gene 4306] {aka MCR, MLR, MR, NR3C2VIT}, Bcl2 (B cell leukemia/lymphoma 2) [NCBI Gene 12043] {aka Bcl-2, C430015F12Rik, D630044D05Rik, D830018M01Rik}, Atg7 (autophagy related 7) [NCBI Gene 312647] {aka Apg7l}, Akt1 (Akt serine/threonine kinase 1) [NCBI Gene 11651] {aka Akt, LTR-akt, PKB, PKB/Akt, PKBalpha, Rac}, Hspa5 (heat shock protein family A (Hsp70) member 5) [NCBI Gene 25617] {aka BIP, GRP 78, GRP78}, FNDC5 (fibronectin type III domain containing 5) [NCBI Gene 252995] {aka FRCP2, irisin}, Lin28a (lin-28 RNA binding posttranscriptional regulator A) [NCBI Gene 500562] {aka Lin28, RGD1566408}, GSK3B (glycogen synthase kinase 3 beta) [NCBI Gene 2932], PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}
- **Diseases:** neurodegeneration (MESH:D019636), Neurotrophic (MESH:D009133), Inflammation (MESH:D007249), cerebral palsy (MESH:D002547), Alzheimer's and Parkinson's diseases (MESH:D010300), emotional disturbances (MESH:D014832), mitochondrial dysfunction (MESH:D028361), AD (MESH:D000544), decline (MESH:D060825), neurological and psychiatric disorders (MESH:D001523), neurotoxic (MESH:D020258), Diabetes (MESH:D003920), HD (MESH:D006816), cerebral ischemia (MESH:D002545), AHN (MESH:D001750), cancer (MESH:D009369), neuroinflammation (MESH:D000090862), schizophrenia (MESH:D012559), anxiety (MESH:D001007), emotional and stress-related disorders (MESH:D000068099), mood disorders (MESH:D019964), neurological disease (MESH:D020271), fatigue (MESH:D005221), impaired spatial learning (MESH:D007859), stroke (MESH:D020521), ischemia (MESH:D007511), major depressive disorder (MESH:D003865), neurological (MESH:D009461), metabolic dysfunction (MESH:D008659), seizure (MESH:D012640), PTSD (MESH:D013313), HIIT (MESH:D000095027), epilepsy (MESH:D004827), brain injury (MESH:D001930), hypertensive (MESH:D006973), colon cancer (MESH:D015179), ischemic injury (MESH:D017202), attention difficulties (MESH:D001289), Toxicity (MESH:D064420), Aging (MESH:D019588), neuronal damage (MESH:D009410), depression (MESH:D003866), dementia (MESH:D003704), neurodevelopmental disorders (MESH:D002658), neuropathological (MESH:D009422), CI (MESH:D003072), chronic (MESH:D002908), compromised spatial memory (MESH:D008569)
- **Chemicals:** fats (MESH:D005223), ginsenosides (MESH:D036145), EGCG (MESH:C045651), lead nitrate (MESH:C017461), BrdU (MESH:D001973), lactate (MESH:D019344), Ginsenoside Rg1 (MESH:C035054), cortisol (MESH:D006854), Quercetin (MESH:D011794), corticosterone (MESH:D003345), carbon-14 (MESH:C000615234), hesperetin (MESH:C013015), iron (MESH:D007501), catechins (MESH:D002392), STZ (MESH:D013311), norepinephrine (MESH:D009638), Resveratrol (MESH:D000077185), blood glucose (MESH:D001786), Rg1 (-), 7,8-dihydroxyflavone (MESH:C485383), hydrogen peroxide (MESH:D006861), Curcumin (MESH:D003474), safranal (MESH:C087963), unsaturated fatty acids (MESH:D005231), soybean oil (MESH:D013024), crocin (MESH:C029036), isoflavones (MESH:D007529), Polyphenol (MESH:D059808), GSH (MESH:D005978), spironolactone (MESH:D013148), beta-alanine (MESH:D015091), LPS (MESH:D008070), lipid (MESH:D008055), naringenin (MESH:C005273), dopamine (MESH:D004298), NAD+ (MESH:D009243), lead (MESH:D007854), morphine (MESH:D009020), arsenic (MESH:D001151), serotonin (MESH:D012701), flavonoid (MESH:D005419), DMSO (MESH:D004121), heavy metal (MESH:D019216), GSK690693 (MESH:C528328)
- **Species:** Malus domestica (apple, species) [taxon 3750], Helianthus annuus (common sunflower, species) [taxon 4232], Mus musculus (house mouse, species) [taxon 10090], Panax ginseng (Asiatic ginseng, species) [taxon 4054], Crocus sativus (saffron crocus, species) [taxon 82528], Rattus norvegicus (brown rat, species) [taxon 10116], Homo sapiens (human, species) [taxon 9606], Curcuma longa (turmeric, species) [taxon 136217], Allium cepa (onion, species) [taxon 4679]
- **Cell lines:** R6/1 — Rattus norvegicus (Rat), Transformed cell line (CVCL_D507)

## Full text

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## References

143 references — full list in the complete paper: https://tomesphere.com/paper/PMC12969489/full.md

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Source: https://tomesphere.com/paper/PMC12969489