#1

This approach had significant benefits for immune function.

The first component the researchers included was AM3, a compound that is core to the Inmunoferon supplement and is an immunomodulator that has been found in trials to aid against infections [1]. Some prior work has found that AM3 also assists against immunosenescence [2]. However, as these researchers note, little work has been done in that area, and that work did not establish whether or not it could do anything to curtail age-related immune dysfunction.

The second component was spermidine, a polyamine that has been reported to improve the cellular maintenance process known as autophagy, thereby also ameliorating immunosenescence [3]. Spermidine has also been reported to assist in gut function by returning macrophage polarization to a less inflammatory state [4].

The third component was hesperidin, a flavonoid that recent prior work had found to have potential effects against multiple diseases, including hepatitis [5] and several metabolism-related disorders, such as diabetes [6], obesity [7], and non-alcoholic fatty liver disease [8]. The researchers hold that these effects most likely originate from its effects against inflammation, such as its suppression of the senescence-related protein MMP-9 [9], and on immune response [10].

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#2

Also

All three of these ingredients are sold in various parts of the world as supplements and are generally considered nontoxic. No side effects were noted in this study.

but

While this was a randomized, controlled trial with significant positive results, it was a pilot trial of only 35 people, not a Phase 2 or larger Phase 3 trial. This trial solely used an immune system-based calculation as a proxy for biological age; no epigenetic clock was used, and other lifespan-related biomarkers were not obtained. Cellular senescence, which the researchers had mentioned and was likely to be affected by the circulating biomarkers studied here, was also not directly analyzed. This study was conducted on a middle-aged group; it is unclear whether or not older people would have responded in the same way.

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#3

Do we know who ran this trial?

#4

The listed references start with this one:

JA, G. M., & Schamann, F. (1992). Immunologic clinical evaluation of a biological response modifier, AM3, in the treatment of childhood infectious respiratory pathology. Allergologia et Immunopathologia , 20 (1), 35-39.

#5

Is this it?

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#6

Interesting and promising yet this seems to complicate the spermidine factor…

High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study

5. Conclusions

The results presented here for the first time provide a pharmacokinetic basis for future translational research on spermidine. Oral spermidine intake of 15 mg/d for 5 days significantly increased spermine levels in the plasma but did not affect spermidine or putrescine levels. Our data strongly suggest that dietary spermidine is presystemically converted into spermine, which then occurs in the systemic circulation. Consequently, we postulate that the in vitro and clinical effects of spermidine are (at least in part) not attributable to spermidine itself but rather to its metabolite, spermine. It is rather unlikely that spermidine supplements with doses <15 mg/d exert any effect. Moreover, even spermidine doses of 15 mg/d do not affect salivary polyamine concentrations; in particular, pharmacological spermidine concentrations in the saliva that, due to preclinical data, might be effective at inhibiting oropharyngeal SARS-CoV-2 replication are not remotely achieved.

Finally, epidemiological studies that have correlated dietary spermidine intake with biological effects are challenged by our results, as such studies have not considered the variability of presystemic spermidine metabolism and dietary spermine intake.