Nanoparticles-based anti-aging treatment of Alzheimer’s disease

Figures & data

Figure 1. Interaction of senescent cells in the CNS.

Table 1. Senolytics and related anti-aging experiments.

Senolytics	Target	Model of experiment
Dasatinib	Ephrins dependent receptor	AD phase II pilot (NCT04063124) (Kirkland & Tchkonia, 2020)
Flavonoid (Quercetin, Fisetin, Luteolin)	Multi targets (MAPK pathway, PI3K/AKT pathway, Bcl-2 family proteins, and so on)	Only Quercetin in AD phase II. Pilot (NCT04063124) (Kirkland & Tchkonia, 2020; Kopustinskiene et al., 2020; Lee et al., 2020)
Curcumin	Multi targets (Bcl-2, Bcl-XL, p38^MAPK, and so on)	More than 250 clinical trials, including AD, cardiovascular diseases, cancer, and so on (Kunnumakkara et al., 2017).
Curcumin analog (EF24)	Bcl-2, Bcl-XL, Mcl-1	Senescent human umbilical vein endothelial cells (HUVEC), senescent fibroblasts, senescent pre-adipocytes, and senescent human renal epithelial cells in vitro (Li et al., 2019).
Piperlongumine	Caspase-mediated apoptosis	Parkinson’s disease animal model (Wang et al., 2016).
Navitoclax (ABT263)	Bcl-2, Bcl-XL	Pathological fibrosis in vivo and vitro (Mohamad Anuar et al., 2020).
A1331852 A1155463	Bcl-XL	Senescent HUVEC in vitro (Zhu et al., 2017).
HSP90 inhibitors	PI3K/AKT pathway	Ercc1 ^−/− murine embryonic fibroblasts in vitro, Ercc1 ^−/Δ mice in vivo (Fuhrmann-Stroissnigg et al., 2017).
FOXO4-DRI	FOXO4/p53 axis	Human testes samples, senescent chondrocytes in vitro (Bourgeois & Madl, 2018).
Nutlin3a	p53	Senescent retinal pigment epithelium cells in an animal model (Chae et al., 2021).
Cardiac glycosides	Na^+/K^+ ATPase, Bcl2 family proteins	Cell models (osteoarthritis, pulmonary fibrosis, SKHep1 liver cancer cells, A549 lung cancer cells) and aging mice (Guerrero et al., 2019; Triana-Martínez et al., 2019).
Fibrates	Peroxisome proliferator-activated receptor alpha (PPARα)	Chondrocytes from cartilage degeneration and osteoarthritis in vitro, clinical retrospective study (Nogueira-Recalde et al., 2019).
Senescence-specific killing compound-1 (SSK1)	p38^MAPK	Senescent mouse embryonic fibroblasts (MEFs), senescent mouse lung fibroblasts, senescent human embryonic fibroblasts (HEFs), senescent HUVEC, lung-injured mice, aged mice (Cai et al., 2020).

Reference annotations:

* doi:10.1002/alz.12328, *doi:10.1038/nm.4000,

** doi:10.1002/adma.201801362,

** doi:10.1111/joim.13141,

** doi:10.1002/advs.202004929,

* doi:10.1101/gad.343129.120,

* doi:10.1056/NEJMra0912273.

Nanoparticles-based anti-aging treatment is a promising therapeutics for AD.

Figure 2. Benefit and detriment of senescent cells. Most of the effects are concerned with the SASP. Different inducements of aging, different types of senescent cells, and different aging stages give rise to these pleiotropic and contradictory effects. Adapted with permission (Birch & Gil, 2020). Copyright 2020, Cold Spring Harbor Laboratory Press.

Figure 3. Six approaches by which agents cross through the BBB. Three such pathways include paracellular transport, passive transcellular diffusion, and CMT. Adapted with permission (Furtado et al., 2018). Copyright 2018, John Wiley and Sons.

Figure 4. Six approaches by which agents cross through the BBB. Three other pathways include AMT, RMT, and cell-mediated transport. Adapted with permission (Furtado et al., 2018). Copyright 2018, John Wiley and Sons.

Kirkland JL, Tchkonia T. (2020). Senolytic drugs: from discovery to translation. J Intern Med 288:518–36.

 PubMed Web of Science ®Google Scholar

Kopustinskiene DM, Jakstas V, Savickas A, Bernatoniene J. (2020). Flavonoids as anticancer agents. Nutrients 12:457.

 PubMed Web of Science ®Google Scholar

Lee J-W, Choi HJ, Kim E-J, et al. (2020). Fisetin induces apoptosis in uterine leiomyomas through multiple pathways. Sci Rep 10:7993.

 PubMed Web of Science ®Google Scholar

Kunnumakkara AB, Bordoloi D, Padmavathi G, et al. (2017). Curcumin, the golden nutraceutical: multi-targeting for multiple chronic diseases. Br J Pharmacol 174:1325–48.

 PubMed Web of Science ®Google Scholar

Li W, He Y, Zhang R, et al. (2019). The curcumin analog EF24 is a novel senolytic agent. Aging (Albany NY) 11:771–82.

 PubMedGoogle Scholar

Wang Y, Chang J, Liu X, et al. (2016). Discovery of piperlongumine as a potential novel lead for the development of senolytic agents. Aging (Albany NY) 8:2915–26.

 PubMedGoogle Scholar

Mohamad Anuar NN, Nor Hisam NS, Liew SL, Ugusman A. (2020). Clinical review: navitoclax as a pro-apoptotic and anti-fibrotic agent. Front Pharmacol 11:564108.

 PubMed Web of Science ®Google Scholar

Zhu Y, Doornebal EJ, Pirtskhalava T, et al. (2017). New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Aging (Albany NY) 9:955–63.

 PubMedGoogle Scholar

Fuhrmann-Stroissnigg H, Ling YY, Zhao J, et al. (2017). Identification of HSP90 inhibitors as a novel class of senolytics. Nat Commun 8:422.

 PubMed Web of Science ®Google Scholar

Bourgeois B, Madl T. (2018). Regulation of cellular senescence via the FOXO4-p53 axis. FEBS Lett 592:2083–97.

 PubMed Web of Science ®Google Scholar

Chae J-B, Jang H, Son C, et al. (2021). Targeting senescent retinal pigment epithelial cells facilitates retinal regeneration in mouse models of age-related macular degeneration. Geroscience 43:2809–33.

 PubMed Web of Science ®Google Scholar

Guerrero A, Herranz N, Sun B, et al. (2019). Cardiac glycosides are broad-spectrum senolytics. Nat Metab 1:1074–88.

 PubMedGoogle Scholar

Triana-Martínez F, Picallos-Rabina P, Da Silva-Álvarez S, et al. (2019). Identification and characterization of Cardiac Glycosides as senolytic compounds. Nat Commun 10:4731.

 PubMed Web of Science ®Google Scholar

Nogueira-Recalde U, Lorenzo-Gómez I, Blanco FJ, et al. (2019). Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy. EBioMedicine 45:588–605.

 PubMed Web of Science ®Google Scholar

Cai L, Yang C, Jia W, et al. (2020). Endo/lysosome-escapable delivery depot for improving BBB transcytosis and neuron targeted therapy of Alzheimer’s disease. Adv Funct Mater 30:1909999.

 Web of Science ®Google Scholar

Birch J, Gil J. (2020). Senescence and the SASP: many therapeutic avenues. Genes Dev 34:1565–76.

 PubMed Web of Science ®Google Scholar

Furtado D, Björnmalm M, Ayton S, et al. (2018). Overcoming the blood-brain barrier: the role of nanomaterials in treating neurological diseases. Adv Mater 30:e1801362.

 PubMed Web of Science ®Google Scholar