# Circadian feeding promotion by Ninjin’yoeito counteracts frailty in aged mice

**Authors:** Lei Wang, Yermek Rakhat, Masanori Nakata, Katsuya Dezaki, Hitoshi Kuwata, Boyang Zhang, Wanxin Han, Seiya Banno, Chikara Abe, Noboru Ogiso, Takashi Sakurai, Shin Tsunekawa, Daisuke Yabe, Yusaku Iwasaki, Yutaka Seino, Toshihiko Yada

PMC · DOI: 10.1016/j.jphyss.2026.100062 · 2026-01-27

## TL;DR

A herbal medicine called Ninjin’yoeito helps reduce frailty in old mice by promoting feeding during a specific time of day.

## Contribution

The study identifies pre-active phase feeding promotion as a novel strategy to counteract aging-related frailty.

## Key findings

- NYT increases food intake in aged and young mice during the pre-active phase (18:00–20:00).
- NYT improves anti-anxiety behavior, memory, and grip strength in aged mice.
- The effects of NYT are blocked when food is restricted during the pre-active phase.

## Abstract

Frailty in aging is a major health challenge, requiring solution. Older people with frailty often exhibit malnutrition and dysregulated feeding. Feeding behavior displays circadian rhythm, while aging and frailty involve rhythm disorders, suggesting possible role of circadian feeding in frailty and treatment. Herbal medicine, Ninjin’yoeito (NYT), reportedly ameliorates frail symptoms. The present study explored impacts of NYT on circadian feeding and psychological/physical functions in aged mice. Here, we report that oral NYT independent of administration timing increases food intake specifically in 18:00–20:00, the pre-active phase, in aged and young mice, an effect mimicked by Chenpi and hesperidin. NYT altered appetite-regulating hormones and neuropeptides in pre-active phase. Repeated NYT administration restored anti-anxiety behavior, memory, and grip strength that declined in aged mice. These effects were blocked by food deprivation and pair-fed to control selectively in 18:00–20:00. These results reveal pre-active phase feeding promotion as a novel avenue to intervene aging-related frailty.

•Circadian feeding promotion by Ninjin’yoeito (NYT) counteracts frailty in old mice.•Critical circadian time for feeding to counteract frailty is the pre-active phase.•NYT alters neurohormones regulating appetite and mind in pre-active phase.•Boosting early morning appetite and breakfast can intervene frailty in old people.•It can be achieved with NYT as medicine and Chenpi/hesperidin as food/supplement.

Circadian feeding promotion by Ninjin’yoeito (NYT) counteracts frailty in old mice.

Critical circadian time for feeding to counteract frailty is the pre-active phase.

NYT alters neurohormones regulating appetite and mind in pre-active phase.

Boosting early morning appetite and breakfast can intervene frailty in old people.

It can be achieved with NYT as medicine and Chenpi/hesperidin as food/supplement.

## Linked entities

- **Chemicals:** hesperidin (PubChem CID 10621)
- **Species:** Mus musculus (taxon 10090)

## Full-text entities

- **Genes:** Trh (thyrotropin releasing hormone) [NCBI Gene 22044] {aka Pro-TRH, Trf}, Pomc (pro-opiomelanocortin-alpha) [NCBI Gene 18976] {aka ACTH, BE, Beta-LPH, Clip, Gamma-LPH, Npp}, Pyy (peptide YY) [NCBI Gene 217212], Bdnf (brain derived neurotrophic factor) [NCBI Gene 12064], Oxt (oxytocin) [NCBI Gene 18429] {aka OT, Oxy}, Gapdh (glyceraldehyde-3-phosphate dehydrogenase) [NCBI Gene 14433] {aka Gapd}, Ldlrap1 (low density lipoprotein receptor adaptor protein 1) [NCBI Gene 100017] {aka ARH2, Arh, Arh1, FHCB1, FHCB2}, Npy (neuropeptide Y) [NCBI Gene 109648] {aka 0710005A05Rik}, Avp (arginine vasopressin) [NCBI Gene 11998] {aka Vp, Vsp}, Crh (corticotropin releasing hormone) [NCBI Gene 12918] {aka CRF, Gm1347}, Gip (gastric inhibitory polypeptide) [NCBI Gene 14607], Gcg (glucagon) [NCBI Gene 14526] {aka GLP-1, Glu, PPG}, Ghrl (ghrelin and obestatin prepropeptide) [NCBI Gene 59301], Adcyap1 (adenylate cyclase activating polypeptide 1) [NCBI Gene 11516] {aka PACAP}, Ghrl (ghrelin) [NCBI Gene 58991] {aka 2210006E23Rik, Ghr, MTLRP, MTLRPAP, m46}, Agrp (agouti related neuropeptide) [NCBI Gene 11604] {aka Agrt, Art}, Gcg (glucagon) [NCBI Gene 24952] {aka GLP-1, Glp1, Glp2}, Gip (gastric inhibitory polypeptide) [NCBI Gene 25040] {aka Gludins, RATGLUDINS}, Nucb2 (nucleobindin 2) [NCBI Gene 53322] {aka Calnuc, Nefa, Nesfatin-1}
- **Diseases:** muscle atrophy (MESH:D009133), fatigue (MESH:D005221), dementia (MESH:D003704), sarcopenia (MESH:D055948), Frailty (MESH:D000073496), Anxiety (MESH:D001007), anorexia (MESH:D000855), rhythm disorders (MESH:D021081), malnutrition (MESH:D044342), insulin resistance (MESH:D007333), Diabetes (MESH:D003920)
- **Chemicals:** fat (MESH:D005223), EnsH (-), dopamine (MESH:D004298), Trizol (MESH:C411644), H (MESH:D006859), DW (MESH:D014867), isoflurane (MESH:D007530), serotonin (MESH:D012701), blood glucose (MESH:D001786), carbohydrate (MESH:D002241), cisplatin (MESH:D002945), hesperidin (MESH:D006569), testosterone (MESH:D013739)
- **Species:** Homo sapiens (human, species) [taxon 9606], Mus musculus (house mouse, species) [taxon 10090], Rattus norvegicus (brown rat, species) [taxon 10116]

## Figures

7 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12874285/full.md

---
Source: https://tomesphere.com/paper/PMC12874285