A Pilot Randomized Controlled Study of Combinatorial Gerotherapeutics for Healthspan Improvement
Phase: PHASE3
Conditions: Healthspan Improvement, Aging, Longevity
Sponsor: AgelessRx

 
 
 
 
Protocol Number: ALRx011v3 
                    Date Amended: December 3, 2025 
Approval Number: IRCM-2025-437             
 Continuing Review Date: September 16, 2026 
 
 
IRCM-2025-437 
Dec. 3, 2025 
 
 
Title: A Pilot Randomized Controlled Study of Combinatorial Gerotherapeutics for Healthspan Improvement 
 
Protocol Number: ALRx011v3 
Version, Date: v3, November 13, 2025 
 
Test Drug: Rapamycin, Low-dose Naltrexone, Metformin, B12, NAD+, GSH, and the Infinite Supplement 
 
Indication: Healthy, normative aging individuals between 60 years of age and 80 years of age seeking 
healthspan biomarker improvement 
 
Study Design: Single-center, prospective, randomized controlled pilot study 
 
 
Study population:  AgelessRx Patients 
 
Site: 
 
 
This is a decentralized trial. Participants can be located in any  
of the 50 states of the USA. All participation will be via  
telemedicine using the AgelessRx website (agelessrx.com) and services.  
 
Sponsor Name, Address, and Telephone Number: 
 
 
 
 
 
 
 
AgelessRx 
Contact: Stefanie Morgan 
Address: 2370 E Stadium Blvd #2049, Ann Arbor, MI 48104 
Phone: 413-563-9686  
Email: stefanie@agelessrx.com 
 
Research Coordinator: 
 
 
 
 
Virginia Lee 
 
 
 
Address: 2370 E Stadium Blvd #2049 Ann Arbor, MI 48104 
 
 
 
Email: Research@agelessrx.com  
 
Principal Investigators: 
 
 
 
 
 
 
 
Jenell Decker, MD 
Address: 2370 E Stadium Blvd #2049, Ann Arbor, MI 48104 
Phone: (650) 503-1889  
Email: drdecker@agelessrx.com 
 
 
 
 
Stefanie Morgan, PhD 
 
 
 
Address: 2370 E Stadium Blvd #2049 Ann Arbor, MI 48104 
 
 
 
Tel: 413-563-9686 
 
 
 
Email: stefanie@agelessrx.com 
 
 
 

 
Protocol Number: ALRx011v3 
                    Date Amended: December 3, 2025 
Approval Number: IRCM-2025-437             
 Continuing Review Date: September 16, 2026 
 
Institutional Review Board of the Institute of Regenerative and Cellular Medicine  
 
James P. Faber  
Tel: 786.271.2156  
Email: jpfaber@ircm.org  
 
 
 Compliance: The study will be conducted in accordance with the standards of    
                                
Good Clinical Practice (GCP), as defined by the International Conference   
                                
on Harmonisation (ICH) and all applicable federal and local regulations. 
 
 
 
Confidential Information 
The information contained within this protocol is confidential and may not be used, divulged, published, or 
otherwise disclosed without the prior written consent of AgelessRx. 
 
 

 
Protocol Number: ALRx011v3 
                    Date Amended: December 3, 2025 
Approval Number: IRCM-2025-437             
 Continuing Review Date: September 16, 2026 
1 Signature Page 
 
I have read this clinical protocol and confirm that to the best of my knowledge, it accurately describes the 
design and conduct of the study titled: A Pilot Randomized Controlled Study of Combinatorial Gerotherapeutics 
for Healthspan Improvement 
 
 
 
 
 
 
Jenell Decker, MD 
 
 
 
 
 
Date: November 13, 2025 
 
 
 
 
 
 
Stefanie Morgan, PhD 
 
 
                 
 Date: November 13, 2025 
 
 
 

 
Protocol Number: ALRx011v3 
                    Date Amended: December 3, 2025 
Approval Number: IRCM-2025-437             
 Continuing Review Date: September 16, 2026 
2 Synopsis  
 
Name of Sponsor/Company: AgelessRx 
Name of product: Rapamycin, Low-dose Naltrexone, Metformin, B12, NAD+, GSH, and Infinite supplement 
Title of study: Pilot Study of the Efficacy of Combination Gerotherapeutics for Healthspan Improvement 
Objectives: 
Primary:  
1. To evaluate the impact of different combinations of gerotherapeutics on measures of muscle, 
cognitive, and immune function. 
Secondary:  
1. To assess the impact of the combinatorial gerotherapeutics on sleep measures, perceived quality of 
life and longevity biomarkers. 
Methodology:   
 
This study is an interventional, randomized, controlled pilot trial exploring multi-modal gerotherapies and their 
impact on longevity-related outcomes.  
 
Potential subjects will be recruited utilizing email and social media-based methods. They will be screened for 
eligibility and enrolled in the study upon obtaining informed consent.  
 
In this proof-of-concept phase, a small sample size of 30 subjects (10 subjects in each arm) will be 
randomized into one of the three arms: 1) Control, 2) Multi-therapy (B12, Naltrexone, Metformin, and NAD+), 
or 4) Comprehensive Therapy (Rapamycin, Naltrexone, Metformin, B12, NAD+, GSH, and Infinite 
Supplement). The intervention period is 90 days. During the first 30 days, subjects will titrate up to 
maintenance dosing regimen of the assigned arm, which will be continued for the 60 days thereafter.  
 
All groups will complete DXA scans, V02 Max tests, Creyos cognitive assessments, Edifice Health's iAge 
tests, iollo at-home blood testing kits, routine blood-work, and the following standardized survey 
questionnaires: ISQ, SF-36, RAPA, and SQS. Subjects will set-up Oura data-tracking for health biometric 
data with study staff assistance. Intervention group participants will also receive a guided meditation program 
and structured exercise program to follow throughout the study. In contrast, participants in the control group 
will engage in a standard exercise regimen (150 minutes per week) and listen to a neutral podcast designed 
to control for time and attention. 
 
Participants will be evaluated at baseline and study end for measures of muscle function (by DXA scan of 
muscle mass and the VO2 max test to measure endurance capacity using a formal test and/or Oura ring 
estimate), cognitive function (by Creyos cognitive tests via web browser), immune function (by iAge and 
CD4+ : CD8+ ratio/lymphocyte : neutrophil ratio with Immune Status Questionnaire (ISQ) supplementation), 
SF-36 Quality of Life (SF-36 QoL) survey scores, PhenoAge (from blood biomarkers obtained from routine 
safety labs, detailed below), activity levels (RAPA questionnaire, Oura ring), metabolic health measures from 
routine and at-home blood tests, sleep improvements evaluated through Oura wearable device sleep quality 
and quantity as well as the Sleep Quality Survey (SQS), as well as other health indicators from Oura 
wearable data between baseline and study end. To ensure robustness of outcome measures, two 
measurements of each item 1 week apart will be used at baseline and again at study end for all measures 
except for DXA scan, V02 max formal test and Oura ring estimate, iAge and iollo kits, which will be used 
once at the beginning and once at the end of the study. 

 
Protocol Number: ALRx011v3 
                    Date Amended: December 3, 2025 
Approval Number: IRCM-2025-437             
 Continuing Review Date: September 16, 2026 
Number of subjects planned: 30 
Diagnosis and main criteria for inclusion: Adults 60-80 years of age who report a BMI of 26-30; SF36 
score below the validated central tendency for 2 of: physical function, physical role limitations, energy, pain; 
final ISQ scores of <6; brain fog or difficulty with mental clarity; pre-diabetic; or who have a similar 
combination of reduced overall health functioning as determined by a physician. 
Statistical analysis: Descriptive statistics for all variables, including outcome measures and adverse events, 
will be reported as mean and standard deviation (SD) for normal data or median and 25th-75th percentiles for 
potential non-normal data. Given the pilot nature of this round of testing, 95% confidence intervals, effect 
sizes, and minimum clinically important difference (MCID) will be utilized to provide a go/no go decision on 
further testing in lieu of formal (an underpowered) statistical hypothesis testing. Effect size and post-hoc 
power will then influence sample size calculations for subsequent rounds of testing. 

 
Protocol Number: ALRx011v3 
                    Date Amended: December 3, 2025 
Approval Number: IRCM-2025-437             
 Continuing Review Date: September 16, 2026 
3 Table of Contents 
 
 
1 Signature Page 
2 
2 Synopsis 
4 
3 Study Design 
5 
4 Table of Contents 
6 
5 List of Abbreviations 
7 
6 Background and Rationale 
8 
6.1 Background on longevity research 
8 
6.2 Background on weight management strategies 
8 
6.3 Hypothesis and goals 
9 
7 Objectives 
10 
7.1 Primary Objective 
10 
7.2 Secondary Objective 
10 
8 Experimental plan 
11 
8.1 Study Design 
11 
8.2 Cost of Participation 
11 
8.3 Estimated Study Duration 
11 
9 Subject Selection 
12 
9.1 Number of Subjects 
12 
9.2 Inclusion Criteria 
12 
9.3 Exclusion Criteria 
12 
9.4 Withdrawal 
12 
10 Schedule of Assessments and Procedures 
13 
10.1 Patient Recruitment 
13 
10.2 Screening 
13 
10.3 Enrollment 
13 
10.4 Evaluations 
13 
10.4.1 Questionnaires 
13 
10.4.2 Routine blood work screenings 
14 
11 Investigational Product 
15 
11.1 Investigational Drug 
15 
11.2 Control Drug 
15 
11.3 Dosing and Administration 
15 
11.3.1 Dose Escalation, Dose Adjustments, Stopping Rules 
15 
11.3.2 Packaging and Labelling 
16 
11.3.3 Storage 
16 
11.4 Concomitant Medications 
17 
12 Adverse Event Reporting 
18 

 
Protocol Number: ALRx011v3 
                    Date Amended: December 3, 2025 
Approval Number: IRCM-2025-437             
 Continuing Review Date: September 16, 2026 
12.1 Adverse Events Definitions 
18 
12.2 Serious Adverse Events 
18 
12.3 Reporting of Adverse Events 
18 
12.3.1 Routine 
18 
12.3.2 Expedited 
19 
13 Statistical Analysis 
20 
14 Ethics 
21 
14.1 Ethical Conduct of the Study 
21 
14.2 Participant Information and Consent 
21 
14.3 Study Participant Confidentiality 
21 
15 Administrative Procedures 
22 
15.1 Modifications to the Protocol 
22 
15.2 Plans for Dissemination of Findings 
22 
16 Reference List 
23 
Appendix A: Informed Consent Forms 
24 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Protocol Number: ALRx011v3 
                    Date Amended: December 3, 2025 
Approval Number: IRCM-2025-437             
 Continuing Review Date: September 16, 2026 
4 List of Abbreviations 
 
Abbreviation 
Definition 
LDN 
Low-dose Naltrexone 
GSH 
Glutathione 
NAD+ 
Nicotinamide Adenine Dinucleotide 
LDR 
Low-dose Rapamycin 
B12 
B12 
SGLT2i 
Sodium-glucose cotransporter-2 inhibitor 
DXA 
Dual-energy X-ray Absorptiometry (Bone Density Test) 
SF-36 
Short Form Health Survey 
ISQ 
Immune Status Questionnaire 
RAPA 
Rapid Assessment of Physical Activity questionnaire 
SQS 
Sleep Quality Survey 
GCP 
Good Clinical Practice 
AE 
Adverse Event 
SAE 
Serious Adverse Event 
ICF 
Informed Consent Form 
IRB 
Institutional Review Board 
PRO  
Patient Reported Outcome 
 
 
 

 
Protocol Number: ALRx011v3 
                    Date Amended: December 3, 2025 
Approval Number: IRCM-2025-437             
 Continuing Review Date: September 16, 2026 
5 Background and Rationale 
5.1 Background on longevity research 
Aging can be defined as a time-dependent functional decline in physiological function that may increase the 
vulnerability to diseases and eventually death. In 2013, a Cell publication defined nine hallmarks of aging (1). 
These hallmarks are genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, 
deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered 
intercellular communication. Age-related diseases, such as cardiovascular diseases and cancer, are major 
causes of morbidity and mortality. Many treatments have been developed and are under development for each 
of these diseases. However, targeting the root cause of these diseases, aging, may decrease the incidence of 
these health issues and increase the quality-adjusted life years (QALY) of large groups of people.  
5.2 Background on gerotherapeutic strategies 
Biological aging is a gradual and heterogeneous process of systemic age-related decline. Unique 
organ-specific aging profiles dictate the pace of aging, from states of optimal health, to pre-disease, clinically 
diagnosed pathology, and ultimately death. A class of drugs, known as gerotherapeutics, are targeted at 
slowing organ aging by targeting the molecular mechanisms that underlie the process, giving rise to the 
hallmarks of aging. As many of these mechanisms are shared between organs, they often target multiple 
organs simultaneously and thus prevent multi-morbidity (2-4).  
Historically, preclinical data has revolved around validating one gerotherapeutic candidate at a time to 
validate its effects on healthy longevity. However, emerging data from multiple labs, including the Intervention 
Testing Program (ITP), suggests that additive, and perhaps even synergistic, benefits may be achieved with 
combinatorial application of drugs having distinct age-related organ or mechanistic targets (5, 6). Similar to 
strategies that have been successfully utilized in effective cancer therapies and cardiovascular interventions, 
multi-therapeutic targeting of biological aging addresses key heterogeneous mechanisms and cellular 
dysfunctions that drive the diversity of age-related decline observed across individuals (7-10). While concerns 
have been raised that the increased potential for adverse side effects with this approach could undermine the 
therapeutic intent, it has not been well-studied to date.  
Available evidence suggests that first generation gerotherapeutic interventions (e.g. FDA-repurposed 
drugs or naturally derived plant chemicals) used as monotherapies are largely insufficient to reverse aging 
substantially, particularly in multiple tissues (10, 11). Second generation gerotherapeutic modalities such as 
therapeutic plasma exchange and epigenetic reprogramming may overcome these challenges, but 
understanding of their use is limited to date, and they are not yet broadly accessible (12). However, it is 
plausible that strategic combinations of first generation gerotherapeutics may accomplish a similar outcome to 
second-generation modalities, but with more readily available and more completely understood medicines. 
Applying these in low doses to optimize safety profiles holds potential to define an early phase of next 
generation gerotherapeutics.  
As such, we hypothesize that repurposing FDA-approved medications for gerotherapeutic applications 
in a combinatorial manner will target the unique aspects of cellular and organ aging biology that are sensitive 
to age-related decline in immune, neural, and musculoskeletal tissue to substantially reverse aging. We will 
test this with increasingly comprehensive combinations of gerotherapeutics (2, 4, and 7), to determine the 
minimum likely effective therapeutic set to improve measures of decline in three experimental study arms and 
a comparative control cohort. This pilot study will predominantly focus on ensuring these approaches are 

 
Protocol Number: ALRx011v3 
                    Date Amended: December 3, 2025 
Approval Number: IRCM-2025-437             
 Continuing Review Date: September 16, 2026 
reasonably safe, and that side effects of combination therapies do not present significant challenges to broader 
implementation for future, more comprehensive studies.  
Our dual-intervention arm includes the most robustly supported gerotherapeutic in the preclinical space, 
low dose rapamycin (LDR), which has been widely suggested to reverse age-related decline of immune, 
cardiovascular, and oral health with self-reported improvements in physical functioning and age-related pain 
(13, 14). However, given the lack of evidence to suggest monotherapies are sufficiently effective in restoring 
multi-organ function across a heterogenously aging population, our dual-intervention arm also includes low 
dose naltrexone (LDN), which has shown broad clinical success for autoimmune and inflammatory conditions 
(15, 16). As evidence is mounting that aging can be broadly considered a process of gradually acquired 
autoimmunity affecting multi-organ function, these promising gerotherapeutics that primarily target 
mechanisms of immune aging form the core of our next generation gerotherapeutic strategy (17). Further, our 
combo and multi-therapeutic arm adds B12 to offer advanced support for a healthy nervous system. (18, 19). 
Finally, our comprehensive therapy arm additionally incorporates glutathione (GSH) and nicotinamide adenine 
dinucleotide (NAD+) supplementation to replenish critical endogenous molecules whose tissue-specific 
depletion is associated with accelerated aging phenotypes in multiple organ systems, and a proprietary 
supplement blend consisting of phytochemicals and metabolites with sufficient coverage to target and address 
all the hallmarks of aging, with the aim of increasing the probability of targeting the critical set of aging 
pathways that sufficiently address the heterogeneity of age-related decline in the target tissues (20-22). 
5.4 Hypothesis and aims 
We hypothesize that repurposing FDA-approved medications for gerotherapeutic applications in a 
combinatorial manner will target the unique aspects of cellular and organ aging biology that are sensitive to 
age-related decline in immune, neural, and musculoskeletal tissue to substantially reverse aging. We will 
investigate this through three aims: 
 
Aim 1: Determine whether LDR and LDN are sufficient to substantially improve healthspan measures of 
cognitive, muscle, and immune function. We hypothesize that the combination of these two pro-longevity 
medications will improve healthspan measures broadly, however, whether they are sufficient to improve all of 
cognitive, muscle, and immune function, or just a subset of these, is unknown. To address this, we will 
evaluate these measures in participants taking LDR and LDN relative to controls. 
 
Aim 2: Identify whether a multi-therapeutic approach improves healthspan more than a 
comprehensive-therapeutic approach. We hypothesize that targeting key elements of healthspan with a 
multi-therapeutic regimen will be more effective in improving healthspan outcomes than a comprehensive-
therapeutic approach. We will thus evaluate healthspan measures of cognitive, muscle, and immune function 
in participants taking a multi-therapeutic intervention relative to comprehensive-therapy intervention. 
 
Aim 3: Establish whether a layered comprehensive therapy approach is necessary for substantial 
healthspan improvement. We hypothesize that multi-faceted targeting of multiple areas of age-related 
declines with both therapeutic interventions and natural supplements will confer superlative healthspan 
benefits relative to other therapeutic approaches. Accordingly, we will test whether adding a proprietary natural 
supplement blend (Infinite), NAD+, and GSH to the multi-therapeutic approach outlined in Aim 2 measurably 
improves healthspan measure outcomes beyond the multi-therapeutic or comprehensive-therapy approaches.  
 

 
Protocol Number: ALRx011v3 
                    Date Amended: December 3, 2025 
Approval Number: IRCM-2025-437             
 Continuing Review Date: September 16, 2026 
We will predominantly focus on ensuring these approaches are reasonably safe, and that side effects of 
combination therapies do not present significant challenges to broader implementation

 
Protocol Number: ALRx011v3 
                    Date Amended: December 3, 2025 
Approval Number: IRCM-2025-437             
 Continuing Review Date: September 16, 2026 
6 Objectives 
6.1 Primary Objective 
1. To evaluate the impact of different combinations of gerotherapeutics on measures of muscle, cognitive, 
and immune function. 
6.2 Secondary Objective 
1. To assess the impact of the combinatorial gerotherapeutics on sleep measures, perceived quality of life 
and longevity biomarkers. 
 
 
 

 
Protocol Number: ALRx011v3 
                    Date Amended: December 3, 2025 
Approval Number: IRCM-2025-437             
 Continuing Review Date: September 16, 2026 
7 Experimental plan 
7.1 Study Design 
Eligible participants will be randomly assigned to one of 3 study arms: multi-therapy, comprehensive therapy, 
or a control. In detail, the arms are:  
● Arm 1 - Multi-Therapy: NAD+, LDN, B12, and metformin 
○ In intervention month one, participants naive to all medications will be titrated on to low 
maintenance doses of each. NAD+ will be taken as a nasal spray of 30mg/day; LDN, will start at 
1.5mg once daily and titrate up each week to 4.5mg daily; B12, take 1 cap per day (100mcg); 
Metformin will be taken 500mg daily. They will then remain on the maintenance doses of the 
combination therapy for the next 60 days.  
● Arm 2 - Comprehensive Therapy: LDR, LDN, B12, metformin, NAD+, GSH, and Infinite 
○ In intervention month one, participants naive to all medications will be titrated on to low 
maintenance doses of each. LDR will start at 2mg once per week and titrate up weekly to 6mg 
once per week; LDN, will start at 1.5mg once daily and titrate up each week to 4.5mg daily; B12, 
take 1 cap per day (100mcg); Metformin will be taken 500mg daily; NAD+ will be taken as a 
nasal spray of 30mg/day; GSH will be taken as a topical patch for 4 hrs, once per week; Infinite 
supplement will be taken once daily. They will then remain on the maintenance doses of the 
combination therapy for the next 60 days.  
● Control: Placebo 
○ In the control cohort, participants will take Vitamin C (1x/day) and Vitamin E (1x/week) as 
placebo agents. 
 
In addition to medications, participants in the intervention groups will engage in a digital guided meditation 
program, while the control group will listen to a neutral podcast to account for time and attention. Participants in 
both intervention groups will also be asked to follow an exercise regimen for improved strength and muscle 
composition, while control participants will be asked to follow a general exercise program. 
 
Participants will be evaluated at baseline and after 90 days on measures of muscle function (by DXA scan of 
muscle mass and VO2 max to measure endurance capacity), cognitive function (by Creyos cognitive tests via 
web browser), immune function (by iAge and CD4+ : CD8+ ratio/lymphocyte : neutrophil ratio with Immune 
Status Questionnaire (ISQ) supplementation), SF-36 Quality of Life (SF-36 QoL) survey scores, activity levels 
from a RAPA questionnaire and Oura ring data, PhenoAge (from blood biomarkers obtained from routine 
safety labs, detailed below), metabolic health measures from routine and at-home testing kits, and sleep 
improvements evaluated through Oura wearable device sleep quality and quantity as well as the Sleep Quality 
Survey (SQS). To ensure robustness of outcome measures, two measurements of each item 1 week apart will 
be used at baseline and again at study end for all measures except DXA/V02 max, iAge and iollo home testing 
kits, which will be used once at the beginning and once at the end of the study. Participants will be provided 
with an Oura ring to wear throughout their study participation. Data collected from the Oura ring will include 
general health metrics such as sleep, physical activity, heart rate, stress, and other relevant health indicators).  
One iollo kit will be given to each participant at study baseline and study conclusion to compare changes in 
metabolic biomarkers of health.  

 
Protocol Number: ALRx011v3 
                    Date Amended: December 3, 2025 
Approval Number: IRCM-2025-437             
 Continuing Review Date: September 16, 2026 
7.2 Cost of Participation 
There are no expected costs to participate.  
7.3 Estimated Study Duration 
Duration: The total duration of the interventional study will be 90 days. An additional 2 months of participant 
recruitment and screening will take place beforehand, and 2 months of data analysis and interpretation will 
follow the conclusion of data acquisition in the interventional study. In total, this work is expected to require 7 
months.  
 
 
 
 

 
Protocol Number: ALRx011v3 
                    Date Amended: December 3, 2025 
Approval Number: IRCM-2025-437             
 Continuing Review Date: September 16, 2026 
8 Subject Selection 
8.1 Number of Subjects 
We will include a total of 30 participants in the analysis. A complete dataset is defined as having a baseline 
score and subsequent response at least 90 days from baseline on all required weight, blood biomarker, and 
survey components of this study design.  
8.2 Inclusion Criteria 
● 
New, existing, or prospective AgelessRx patient 
● 
Adults (60-80 years of age) 
● 
Any sex 
● 
Any ethnicity 
● 
Willingness to provide informed consent and complete study assessments/procedures 
● 
Willingness to attend virtual meeting check-ins/follow-ups 
● 
Willingness and eligibility to take all medications used in this study 
● 
Has at-risk indicators for decline on measures of cognitive, immune, and muscle function, as indicated 
by a combination of BMI of 26-30; SF36 score below the validated central tendency for 2 of: physical 
function, physical role limitations, energy, pain; final ISQ scores of <6; individuals that report brain fog 
or difficulty with mental clarity; pre-diabetic, or other comorbidities that result in reduced overall health 
functioning as determined by a physician 
8.3 Exclusion Criteria 
● 
Pregnant or breastfeeding individuals 
● 
History of severe adverse reactions to study medications 
● 
Significant psychiatric illness that may affect participation 
● 
Determination of ineligibility for a study medication by AgelessRx medical team 
● 
Concurrent participation in other conflicting clinical trials 
8.4 Withdrawal  
● Patients are free to withdraw from the study at any time. 
 
 
 
 
 

 
Protocol Number: ALRx011v3 
                    Date Amended: December 3, 2025 
Approval Number: IRCM-2025-437             
 Continuing Review Date: September 16, 2026 
9 Schedule of Assessments and Procedures 
9.1 Patient Recruitment 
Research participant recruitment for this interventional trial will be initiated through a general marketing 
campaign using email, social media, and similar outreach channels commonly employed for research 
recruitment by the AgelessRx team. Interested individuals will be directed to complete a screening 
questionnaire to assess their initial eligibility and to receive detailed information about the study, including the 
interventions, procedures, potential risks, information about the eligibility screening process, and the informed 
consent form. Participants will also be provided with a link to schedule a virtual meeting with the study 
coordinator to address any questions. 
9.2 Screening 
Patients interested in participating have been screened for eligibility criteria by AgelessRx medical staff via the 
telemedicine platform. The medical intake and consent built into the patient process will include 
inclusion/exclusion screening criteria and will serve as a screening tool for medical and research personnel. 
The consent language built into the patient intake workflow can be found in Appendix A.  
9.3 Enrollment 
Participants will be enrolled in the study for a total of 90 days. In the first 30 days, they will complete baseline 
testing and begin to titrate on to study medications. In the subsequent 60 days, they will continue on the new 
medication regimen (as determined by trial arm).  
9.4 Evaluations 
Primary outcomes assessed will be changes in muscle function (by DXA scan of muscle mass and VO2 max to 
measure endurance capacity), cognitive function (by Creyos cognitive testing), and immune function (by 
Edifice Health's iAge test and CD4+ : CD8+ ratio/lymphocyte : neutrophil ratio with Immune Status 
Questionnaire (ISQ) supplementation) from baseline to study end. To ensure robustness of outcome 
measures, two measurements of each item 1 week apart will be used at baseline and again at study end for all 
measures except DEXA/V02 max, iAge and iollo kits, which will be used once at the beginning and once at the 
end of the study. 
 
Secondary outcomes assessed will be changes in measures of SF-36 Quality of Life (SF-36 QoL) survey 
scores, physical activity levels from a RAPA questionnaire and Oura ring data, PhenoAge (from blood 
biomarkers obtained from routine safety labs, detailed below), metabolic health measures from iollo testing 
kits, and sleep improvements evaluated through Oura wearable device sleep quality and quantity as well as 
the Sleep Quality Survey (SQS) between baseline and study end. Two measurements of SF-36 QoL, 
PhenoAge, and SQS will be conducted 1 week apart at baseline and study end to ensure robustness of 
outcome measures. Relevant health indicators such as sleep, physical activity, heart rate, stress, and VO2 
max estimates will also be assessed using Oura wearable data. One iollo kit will be given to each participant at 
baseline and study end to compare changes in metabolic biomarkers of health.  
 
 

 
Protocol Number: ALRx011v3 
                    Date Amended: December 3, 2025 
Approval Number: IRCM-2025-437             
 Continuing Review Date: September 16, 2026 
9.5 Schedule of Events 
 
Schedule of Events  
Time Point (+/- 
1 week) 
 
Event 
Arms 1-4 (Dual, Multi, Comprehensive Therapy and Control) 
Day 0 
(Baseline) 
Baseline 
Assessments  
Complete medical intake, medical history and demographics. 
Begin intervention or placebo regimen as described for respective arms. 
Complete DXA scan, VO2 max (formally administered test and estimated with 
Oura ring), Creyos, Edifice Health's iAge test, iollo, routine blood-work, ISQ, 
SF-36, RAPA, and SQS. Set-up Oura data-tracking with study staff assistance. 
 
 
Day 1-7 
Medication Titration: 
Week 1 
Multi-Therapy: LDN: 1.5mg/day, Metformin: 500mg daily, NAD+: 30mg/day 
(nasal spray), B12 1/day. 
Comprehensive Therapy: As above + LDR 2mg/week, NAD+: 30mg/day (nasal 
spray), GSH: 4hr patch/week, Infinite: 1/day.  
Placebo: Titration as per Multi-Therapy, but with placebo. 
Control: Vitamin C 1x/day, Vitamin E once a week on same day 
Day 8-14 
Medication Titration: 
Week 2 
Multi-Therapy: LDN 1.5mg/day, Metformin: 500mg daily, NAD+: 30mg/day 
(nasal spray), B12 1/day. 
Comprehensive Therapy: As above + LDR 4mg/week, NAD+: 30mg/day (nasal 
spray), GSH: 4hr patch/week, Infinite: 1/day.  
Control: Vitamin C 1x/day, Vitamin E  once a week on same day 
Day 15-21 
Medication Titration: 
Week 3 
Multi-Therapy: LDN 3mg/day, Metformin: 500mg daily, NAD+: 30mg/day (nasal 
spray), B12 1/day. 
Comprehensive Therapy: As above + LDR 6mg/week, NAD+: 30mg/day (nasal 
spray), GSH: 4hr patch/week, Infinite: 1/day. 
Control: Vitamin C 1x/day, Vitamin E  once a week on same day 
Day 22-28 
Medication Titration: 
Week 4 
Multi-Therapy: LDN 4.5mg/day, Metformin: 500mg daily, Metformin: 500mg 
daily, NAD+: 30mg/day (nasal spray), B12 1/day. 
Comprehensive Therapy: As above + continued NAD+, GSH, Infinite, LDR. 
Control: Vitamin C 1x/day, Vitamin E  once a week on same day 
Day 29-85 
Medication 
Maintenance: Week 
5-12 
Multi-Therapy: Continue on LDN 4.5mg/day, Metformin: 500mg daily, 
Metformin: 500mg daily, NAD+: 30mg/day (nasal spray), B12 1/day. 
Comprehensive Therapy: As above + continued NAD+, GSH, Infinite, LDR. 
Control: Vitamin C 1x/day, Vitamin E  once a week on same day 

 
Protocol Number: ALRx011v3 
                    Date Amended: December 3, 2025 
Approval Number: IRCM-2025-437             
 Continuing Review Date: September 16, 2026 
Day 85-90 
Final Assessments 
(90-Day Visit)  
All groups: Complete DXA scan, VO2 max (formal test and with Oura ring), 
Creyos, Edifice Health's iAge test, iollo, routine blood-work, ISQ, SF-36, RAPA, 
SQS, final assessments, data collection and study exit procedures. 
10 Investigational Product 
10.1 Investigational Drugs 
Rapamycin: a well-known inhibitor of mTOR function, which promotes a cellular state of repair and improved 
cellular stress resistance characterized by enhanced autophagy, improved mitochondrial function, reduced 
chronic inflammation and enhanced adaptive immune function (23). 
 
Low-dose Naltrexone: a synthetic non-selective opioid receptor antagonist, activates both the NRF-2 
transcription factor to regulate anti-oxidant gene expression, cellular stress resilience, and anti-inflammatory 
effects, as well as toll-like receptor 4 (TLR4), to reduce aging-associated chronic inflammation (24); (25) 
 
Metformin: lowers blood sugar levels primarily by blocking the production of glucose by gluconeogenesis. 
Metformin may also work by increasing the ability of skeletal muscle to remove glucose from the bloodstream 
and use it for energy. (26).  
 
Methylcobalamin/vitamin B12: is generally referred to as the cobalamins, with cyanocobalamin as the most 
common form. Recent research has indicated that methylcobalamin provides an enhanced ability to support 
neurological function. Methylcobalamin helps maintain healthy glutamate activity in the brain, providing support 
for healthy brain cell activity. Methylcobalamin may also promote protein synthesis for healthy nerve cell 
maintenance. As a result, methylcobalamin has been shown to encourage healthy cognitive, memory, 
emotional, and nerve function. Methylcobalamin offers advanced support for a healthy nervous system (27).  
 
NAD+: a critical coenzyme involved in over 500 metabolic reactions, essential for DNA repair, epigenetic 
maintenance, mitochondrial health, and regulating healthy immune function (28).  
 
GSH: referred to as the master antioxidant with its primary function in managing oxidative stress and 
preventing free radical damage. Decreased GSH levels are associated with a wide range of age-related 
diseases, including neurodegenerative disorders (29) 
 
Together, NAD+ and GSH are critical enhancing organ health and resilience in physiologically compromised 
populations, supplementation in elderly individuals is associated with salient improvements in cognitive and 
physical function within relatively short timeframes (30-33). 
 
Infinite supplement: a proprietary blend of seven putative geroprotective compounds implicated in enhancing 
cellular function critical for managing cellular damage accumulation prevention of age-related decline (including 
Alpha ketoglutarate, Quercetin, Glucosamine, Carnosine, Pterostilbene,  Astaxanthin, and Curcumin) (34, 35) 

 
Protocol Number: ALRx011v3 
                    Date Amended: December 3, 2025 
Approval Number: IRCM-2025-437             
 Continuing Review Date: September 16, 2026 
10.2 Control Drug 
Vitamins C and E will be utilized as control supplements for this experiment. Vitamin C is vital for building and 
repairing tissues, producing collagen, and supporting the immune system. Vitamin E is a fat-soluble antioxidant 
that protects cells from damage and supports immune function. 
 
10.3 Dosing and Administration 
11.3.1 Dose Escalation, Dose Adjustments, Stopping Rules 
● Arm 1 - Multi-Therapy: LDN, B12, NAD+, and metformin 
○ In intervention month one, participants naive to all medications will be titrated on to low 
maintenance doses of each. NAD+ will be taken as a nasal spray of 30mg/day; LDN, will start at 
1.5mg once daily and titrate up each week to 4.5mg daily; B12 will be taken 1x daily; Metformin 
will be taken 500mg daily. They will then remain on the maintenance doses of the combination 
therapy for the next 60 days.  
● Arm 2 - Comprehensive Therapy: LDR, LDN, B12, metformin, NAD+, GSH, and Infinite 
○ In intervention month one, participants naive to all medications will be titrated on to low 
maintenance doses of each. LDR will start at 2mg once per week and titrate up weekly to 6mg 
once per week; LDN, will start at 1.5mg once daily and titrate up each week to 4.5mg daily; B12 
will be taken 1x daily; Metformin will be taken 500mg daily; NAD+ will be taken as a nasal spray 
of 30mg/day; GSH will be taken as a topical patch for 4 hrs, once per week; Infinite supplement 
will be taken once daily. They will then remain on the maintenance doses of the combination 
therapy for the next 60 days.  
● Control: Placebo 
○ In the control cohort, participants are assigned to take Vitamin C 1x/day and Vitamin E 1x/week 
on the same day each week. 
 
At the trial conclusion, participants may choose to continue with the medications by transferring care to 
AgelessRx, or titrating off of the medications. Those choosing to titrate off will be supervised by an 
AgelessRx physician until medications have all been safely discontinued.   
11.3.2 Packaging and Labeling 
Compounds will be dispensed by the following pharmacies according to state availability:  
Everwell Specialty Pharmacies 
6506 N Davis Hwy, Pensacola, FL 32504 
 
Innovation Pharmaceuticals Inc. 
301 Edgewater Pl Suite 100, Wakefield, MA 01880 
 
Precision Pharmacy 
2640 Merrick Road, Bellmore, NY, 11710 
 
Valiant Compounding Pharmacy 

 
Protocol Number: ALRx011v3 
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Approval Number: IRCM-2025-437             
 Continuing Review Date: September 16, 2026 
1274 Anna J. Stepp Dr, Ypsilanti, MI 48197 
 
Curexa 
3007 Ocean Heights Ave, Egg Harbor Township, NJ 08234 
 
Tailor Made Pharmacy 
200 Moore Dr, Nicholasville, KY 40356 
 
Fullscript 
www.fullscript.com 
 
 
Labeling and packaging will be handled by the entities listed above. 
 
11.3.3 Storage 
Tablets should be stored according to pharmacy instructions, provided on the container for each 
medication.  
11.4 Concomitant Medications 
If participants fit eligibility criteria but are on other medications, they should be continuing to take those 
at the prescribed dosages. They will be instructed to tell their other physicians, medical providers, and 
pharmacists of their enrollment in the trial. Any changes to concomitant medications or any planned 
surgery should be discussed with the PI immediately.

 
Protocol Number: ALRx011v3 
                    Date Amended: December 3, 2025 
Approval Number: IRCM-2025-437             
 Continuing Review Date: September 16, 2026 
11 Adverse Event Reporting 
11.1 Adverse Events Definitions 
 
Adverse drug reaction (ADR): a noxious and unintended reaction to a drug at doses normally used in humans 
for prophylaxis, diagnosis, therapy of diseases, or for the modification of physiological function. A causal 
relationship is at least reasonably possible. 
 
Adverse event (AE): an adverse occurrence experienced by a study subject during the course of the clinical 
trial that is not necessarily associated with the drug. An AE can, therefore, be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the 
investigational product, whether or not related to the investigational product. When an AE has been determined 
to be related to the investigational product, it is considered an adverse drug reaction. 
11.2 Serious Adverse Events 
An adverse event (AE) or suspected adverse reaction is considered “serious” if, in the view of the investigator, 
it results in any of the following outcomes: death, a life- threatening adverse event, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions, or a congenital anomaly/birth defect. Important medical events that may 
not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the participant and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  
 
Adverse events will be graded according to the system below: 
 
Grade 1: Asymptomatic or mild symptoms; clinical or diagnostic observations only; no intervention 
indicated (e.g. headache, nausea, abdominal discomfort) 
 
Grade 2: Moderate; minimal, local or noninvasive intervention (e.g. vomiting, diarrhea, shortness of 
breath) 
 
Grade 3: Severe; or medically significant but not immediately life threatening; hospitalization or 
prolongation of hospitalization indicated; disabling (e.g. dehydration, hypotension) 
 
Grade 4: Life-threatening ; urgent intervention indicated (e.g. respiratory failure, myocardial infarction, 
liver failure) 
 
Grade 5: Death related to an AE 
 
 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines will be 
used to describe severity: 

 
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Approval Number: IRCM-2025-437             
 Continuing Review Date: September 16, 2026 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily activities. 
 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug therapy or 
other treatment. Severe events are usually potentially life-threatening or incapacitating. Of note, the 
term “severe” does not necessarily equate to “serious”. 
 
All adverse events (AEs) must have their relationship to study intervention assessed by the research team 
clinician who examines and evaluates the participant based on temporal relationship and his/her clinical 
judgment. The degree of certainty about causality will be graded using the categories below. 
Related – The AE is known to occur with the study intervention, there is a reasonable possibility that 
the study intervention caused the AE, or there is a temporal relationship between the study intervention 
and event. Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study intervention and the AE. 
 
Not Related – There is not a reasonable possibility that the administration of the study intervention 
caused the event, there is no temporal relationship between the study intervention and event onset, or 
an alternate etiology has been established. 
11.3 Reporting of Adverse Events 
11.3.1 Routine 
The principal investigator will be notified about any adverse events. This information will be obtained 
through monitoring forms, emails, check-in surveys, and/or virtual visits. 
 
The Principal Investigator and clinical trial staff will document this information in the participant’s 
medical record. Participants will be asked to report any serious adverse event immediately to the 
Principal Investigator, this can be done by email or phone (after hours phone number available). 
 
AEs will be documented using standard AE reporting (FDA regulations 21CFR314.80 and 
21CFR213.32(s)). Both expected (already known) and unexpected AEs will be reported. 
11.3.2 Expedited 
Serious adverse events that occur while the research participant is actively participating in the research 
study will be reported to the IRB within 48 hours for the duration of the study (until study is closed at the 
IRB).

 
Protocol Number: ALRx011v3 
                    Date Amended: December 3, 2025 
Approval Number: IRCM-2025-437             
 Continuing Review Date: September 16, 2026 
12 Statistical Analysis 
Scores and responses from questionnaires will be compared across demographic information, history of use, 
reasons for use, etc., and analyzed in combination with biomarker and wearable data, as available. Descriptive 
statistics for all variables, including outcome measures and adverse events, will be reported as mean and 
standard deviation (SD) for normal data or median and 25th-75th percentiles for potential non-normal data. 
Given the pilot nature of this round of testing, 95% confidence intervals, effect sizes, and minimum clinically 
important difference (MCID) will be utilized to provide a go/no go decision on further testing in lieu of formal (an 
underpowered) statistical hypothesis testing. Effect size and post-hoc power will then influence sample size 
calculations for subsequent rounds of testing. 
 
 
 
 

 
Protocol Number: ALRx011v3 
                    Date Amended: December 3, 2025 
Approval Number: IRCM-2025-437             
 Continuing Review Date: September 16, 2026 
13 Ethics 
13.1 Ethical Conduct of the Study 
The study and any amendments will be reviewed by an Institutional Review Board (IRB). The study will be 
conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki. The 
study will be conducted in accordance with good clinical practices (GCP). 
13.2 Participant Information and Consent 
Informed consent will be obtained for all subjects enrolled in the study. Participants will receive a digital PDF 
version of the informed consent documentation associated with the study (Appendix A). Participants will have 
the opportunity to ask questions before signing. Participants will respond to individual lines with Yes or No to 
indicate each section was read and understood, and then sign it electronically. A study coordinator will ensure 
the participants have completed the consent form and have agreed to understanding the study and 
implications of being a participant. It will be stressed that: 
 
1) No benefits of any kind can be expected from participation in this trial 
2) The subjects may withdraw from the trial at any time without a penalty of any kind 
3) There may be risks associated with participating in the trial 
 
Consent will be documented by a free text first and last name field confirming the participant understands the 
study. Identity will be validated by way of state-issued ID upload alongside an image of the participant. All 
participants will be provided a PDF version of the consent form for their reference and storage. 
13.3 Study Participant Confidentiality 
All study records for analysis will be de-identified, so that records cannot be directly linked to the participant 
and are only linked to the participant via coded identifiers. Data will be stored on a password-protected HIPAA-
compliant cloud service. 

 
Protocol Number: ALRx011v3 
                    Date Amended: December 3, 2025 
Approval Number: IRCM-2025-437             
 Continuing Review Date: September 16, 2026 
14 Administrative Procedures 
14.1 Modifications to the Protocol 
Modifications to the protocol will be added to the Clinical Study Protocol and communicated with the IRB. 
 
14.2 Plans for Dissemination of Findings 
We intend to disseminate the findings primarily in five ways: 
1) Publications in peer-reviewed medical journals 
2) Lectures at scientific conferences 
3) Lectures at non-scientific public events 
4) Announcements via the AgelessRx website 
5) Outreach to various media outlets 
 
 
 
 
 
 

 
Protocol Number: ALRx011v3 
                    Date Amended: December 3, 2025 
Approval Number: IRCM-2025-437             
 Continuing Review Date: September 16, 2026 
15 Reference List 
 
1. American Diabetes A. 8. Obesity Management for the Treatment of Type 2 Diabetes: Standards of 
Medical Care in Diabetes-2019. Diabetes Care. 2019;42(Suppl 1):S81-S9. 
2. Tian YE, Cropley V, Maier AB, Lautenschlager NT, Breakspear M, Zalesky A. Heterogeneous aging 
across multiple organ systems and prediction of chronic disease and mortality. Nat Med. 
2023;29(5):1221-31. 
3. Li Y, Wang Q, Xuan Y, Zhao J, Li J, Tian Y, et al. Investigation of human aging at the single-cell level. 
Ageing Res Rev. 2024;101:102530. 
4. Ahadi S, Zhou W, Schussler-Fiorenza Rose SM, Sailani MR, Contrepois K, Avina M, et al. Personal 
aging markers and ageotypes revealed by deep longitudinal profiling. Nat Med. 2020;26(1):83-90. 
5. Strong R, Miller RA, Cheng CJ, Nelson JF, Gelfond J, Allani SK, et al. Lifespan benefits for the 
combination of rapamycin plus acarbose and for captopril in genetically heterogeneous mice. Aging 
Cell. 2022;21(12):e13724. 
6. Gkioni L, Nespital T, Monzó C, Bali J, Nassr T, Cremer AL, et al. A combination of the geroprotectors 
trametinib and rapamycin is more effective than either drug alone. bioRxiv. 2024:2024.07.25.605097. 
7. Jabbour SK, Kumar R, Anderson B, Chino JP, Jethwa KR, McDowell L, et al. Combinatorial 
Approaches for Chemotherapies and Targeted Therapies With Radiation: United Efforts to Innovate in 
Patient Care. Int J Radiat Oncol Biol Phys. 2024;118(5):1240-61. 
8. Wang N, Rueter P, Atkins E, Webster R, Huffman M, de Silva A, et al. Efficacy and Safety of Low-Dose 
Triple and Quadruple Combination Pills vs Monotherapy, Usual Care, or Placebo for the Initial 
Management of Hypertension: A Systematic Review and Meta-analysis. JAMA Cardiol. 2023;8(6):606-
11. 
9. Li X, Peng X, Zoulikha M, Boafo GF, Magar KT, Ju Y, et al. Multifunctional nanoparticle-mediated 
combining therapy for human diseases. Signal Transduct Target Ther. 2024;9(1):1. 
10. Panchin AY, Ogmen A, Blagodatski AS, Egorova A, Batin M, Glinin T. Targeting multiple hallmarks of 
mammalian aging with combinations of interventions. Aging (Albany NY). 2024;16(16):12073-100. 
11. Parkhitko AA, Filine E, Tatar M. Combinatorial interventions in aging. Nat Aging. 2023;3(10):1187-200. 
12. Lyu Y FQ, Wilczok D, Ying K, King A, Antebi A, Vojta A, Stolzing A, Moskalev A, Georgievskaya A, 
Maier AB, Olsen A, Groth A, et al. Longevity biotechnology: bridging AI, biomarkers, geroscience and 
clinical applications for healthy longevity. Aging (Albany NY). 2024;16(20). 
13. Kaeberlein TL, Green AS, Haddad G, Hudson J, Isman A, Nyquist A, et al. Evaluation of off-label 
rapamycin use to promote healthspan in 333 adults. Geroscience. 2023;45(5):2757-68. 
14. Mannick JB, Lamming DW. Targeting the biology of aging with mTOR inhibitors. Nat Aging. 
2023;3(6):642-60. 
15. Toljan K, Vrooman B. Low-Dose Naltrexone (LDN)-Review of Therapeutic Utilization. Med Sci (Basel). 
2018;6(4). 
16. Younger J, Parkitny L, McLain D. The use of low-dose naltrexone (LDN) as a novel anti-inflammatory 
treatment for chronic pain. Clin Rheumatol. 2014;33(4):451-9. 
17. Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. Inflammaging: a new immune-metabolic 
viewpoint for age-related diseases. Nat Rev Endocrinol. 2018;14(10):576-90. 
18. Rojas JC, Bruchey AK, Gonzalez-Lima F. Neurometabolic mechanisms for memory enhancement and 
neuroprotection of methylene blue. Prog Neurobiol. 2012;96(1):32-45. 

 
Protocol Number: ALRx011v3 
                    Date Amended: December 3, 2025 
Approval Number: IRCM-2025-437             
 Continuing Review Date: September 16, 2026 
19. La Grotta R, Frige C, Matacchione G, Olivieri F, de Candia P, Ceriello A, et al. Repurposing SGLT-2 
Inhibitors to Target Aging: Available Evidence and Molecular Mechanisms. Int J Mol Sci. 2022;23(20). 
20. McReynolds MR, Chellappa K, Baur JA. Age-related NAD(+) decline. Exp Gerontol. 2020;134:110888. 
21. Chen Y, Hamidu S, Yang X, Yan Y, Wang Q, Li L, et al. Dietary Supplements and Natural Products: An 
Update on Their Clinical Effectiveness and Molecular Mechanisms of Action During Accelerated 
Biological Aging. Front Genet. 2022;13:880421. 
22. Iskusnykh IY, Zakharova AA, Pathak D. Glutathione in Brain Disorders and Aging. Molecules. 
2022;27(1). 
23. Papadopoli D, Boulay K, Kazak L, Pollak M, Mallette F, Topisirovic I, et al. mTOR as a central regulator 
of lifespan and aging. F1000Research. 2019;8:998. 
24. Li W, Mcintyre LR, Schomakers VB, Kamble R, Luesink HGA, Weeghel VM, et al. Low-dose naltrexone 
extends healthspan and lifespan in C. elegans via SKN-1 activation. iScience. 2024;27(6):109949. 
25. Younger J, Parkitny L, Mclain D. The use of low-dose naltrexone (LDN) as a novel anti-inflammatory 
treatment for chronic pain. Clinical Rheumatology. 2014;33(4):451-9. 
26. Grotta LR, Frigé C, Matacchione G, Olivieri F, Candia DP, Ceriello A, et al. Repurposing SGLT-2 
Inhibitors to Target Aging: Available Evidence and Molecular Mechanisms. International Journal of 
Molecular Sciences. 2022;23(20):12325. 
27. Xue H, Thaivalappil A, Cao K. The Potentials of Methylene Blue as an Anti-Aging Drug. Cells. 
2021;10(12):3379. 
28. Chini CCS, Cordeiro HS, Tran NLK, Chini EN. <scp>NAD</scp> metabolism: Role in senescence 
regulation and aging. Aging Cell. 2024;23(1). 
29. Takujiro H, Junichi F. Application of Glutathione as Anti-Oxidative and Anti-Aging Drugs. Current Drug 
Metabolism. 2015;16(7):560-71. 
30. Iskusnykh YI, Zakharova AA, Pathak D. Glutathione in Brain Disorders and Aging. Molecules. 
2022;27(1):324. 
31. Aoi W, Ogaya Y, Takami M, Konishi T, Sauchi Y, Park YE, et al. Glutathione supplementation 
suppresses muscle fatigue induced by prolonged exercise via improved aerobic metabolism. Journal of 
the International Society of Sports Nutrition. 2015;12(1):7. 
32. Campbell MJ. Supplementation with NAD+ and Its Precursors to Prevent Cognitive Decline across 
Disease Contexts. Nutrients. 2022;14(15):3231. 
33. Igarashi M, Nakagawa-Nagahama Y, Miura M, Kashiwabara K, Yaku K, Sawada M, et al. Chronic 
nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels 
and alters muscle function in healthy older men. npj Aging. 2022;8(1). 
34. Chen Y, Hamidu S, Yang X, Yan Y, Wang Q, Li L, et al. Dietary Supplements and Natural Products: An 
Update on Their Clinical Effectiveness and Molecular Mechanisms of Action During Accelerated 
Biological Aging. Frontiers in Genetics. 2022;13. 
35. Sharma A, Chabloz S, Lapides AR, Roider E, Ewald YC. Potential Synergistic Supplementation of 
NAD+ Promoting Compounds as a Strategy for Increasing Healthspan. Nutrients. 2023;15(2):445.

 
Protocol Number: ALRx011v3 
                    Date Amended: December 3, 2025 
Approval Number: IRCM-2025-437             
 Continuing Review Date: September 16, 2026 
Informed Consent Form 
 
Consent to Participate in a Research Study 
Study Title: A Pilot Randomized Controlled Study of Combinatorial Gerotherapeutics for Healthspan 
Improvement 
Sponsor: AgelessRx, Inc.  
            Address: 2370 E Stadium Blvd #2049 Ann Arbor, MI 48104  
Tel: 650-503-9990  
Fax: 650-729-0869  
Email: info@agelessrx.com  
Principal Investigators:  
 
Jenell Decker, MD 
Address: 2370 E Stadium Blvd #2049, Ann Arbor, MI 48104 
Phone: (650) 503-1889  
Email: drdecker@agelessrx.com 
 
Stefanie Morgan, PhD 
 
 
 
Address: 2370 E Stadium Blvd #2049 Ann Arbor, MI 48104 
 
 
 
Tel: 413-563-9686 
 
 
 
Email: stefanie@agelessrx.com 
 
 
Site: This is a decentralized trial. Participants can be located in any of the 50 states of the USA. 
All participation will be via telemedicine using the AgelessRx website (agelessrx.com) and 
services.  
Key Information 
 
What should I know about a research study? 
 
• 
You can choose whether or not to take part. 
• 
You can agree to take part and then later change your mind. 
• 
Your decision whether or not to participate will not be held against you. 
• 
You can ask all the questions you want before you decide. 
What is the purpose, procedures and duration of this study?  
We invite you to take part in a research study because you have shown interest in improving at-risk healthspan 
indicators for decline on measures of cognitive, immune, and muscle function or reduced overall health 
functioning as determined by a physician. The purpose of this study is to evaluate combinations of known 
gerotherapeutics to identify a minimum regimen that substantially improves cognitive, muscle, and immune 
functions. These combinational modalities are investigational (experimental). The interventions are approved 
by the Food and Drug Administration (FDA) separately; however, they are not approved as combinatorial 
modalities which this study aims to explore.  

 
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                    Date Amended: December 3, 2025 
Approval Number: IRCM-2025-437             
 Continuing Review Date: September 16, 2026 
You will be assigned to one of the interventional or control arms for 90 days. Once assigned, you will follow a 
titration (increase per week) regimen for that arm, instructed by the research team, for the first 30 days. After 
the first 30 days, you will remain with a steady regimen for 60 days thereafter. You will be asked to complete 
questionnaires, cognitive testing, blood samples, a digital guided meditation program, exercise program, DXA 
body imaging scans and VO2 max tests. You will also be asked to provide Oura ring wearable health data to 
track healthspan measures. 
Your participation in the research will last about 90 days. 
Why might you choose not to participate in this research study? 
The study may involve risks, including but not limited to gastrointestinal discomfort, changes in mood, and 
other side effects associated with the alternative therapies. See Risks for more details. 
What are my other choices if I do not take part in this study? 
The alternative to being in this study is to not take part.  
Do the researchers or institution have any conflicts of interest relating to this study? 
One or more of the Investigators conducting this study serve as consultants or employees for the company that 
makes products used in this study. These financial interests are within permissible limits established by the 
local institutional Conflict of Interest Policy. If you have any questions regarding conflicts of interest, please ask 
your study doctor. 
Detailed Information 
How Many People Will Take Part in this Study? 
Approximately 30 people will take part in this study. 
What is involved if you decide to take part in this research study? 
Study Terms: 
● Randomization: a process will be used to assign you, by chance, to one of the study groups. Neither 
you nor your doctor can choose which group you are in. 
● Low-dose Rapamycin (LDR): This is a treatment using a very small amount of rapamycin, a drug that 
helps slow down the aging process by blocking certain pathways in the body that contribute to 
inflammation and cell damage. LDR may improve health, extend lifespan, and support tissue repair. 
● Low-dose Naltrexone (LDN): This involves taking a small dose of naltrexone, a drug that normally treats 
addiction. At low doses, it may help boost the immune system, reduce inflammation, and relieve 
symptoms of autoimmune diseases, chronic pain, and other conditions. 
● B12: Recent research has indicated that methylcobalamin provides an enhanced ability to support 
neurological function. Methylcobalamin helps maintain healthy glutamate activity in the brain, providing 
support for healthy brain cell activity. Methylcobalamin may also promote protein synthesis for healthy 
nerve cell maintenance. As a result, methylcobalamin has been shown to encourage healthy cognitive, 
memory, emotional, and nerve function. Methylcobalamin offers advanced support for a healthy 
nervous system.. 
● Metformin: Metformin is a medication used to help people with type 2 diabetes to manage their blood 
sugar levels. Metformin lowers blood sugar levels primarily by blocking the production of glucose by the 
liver, a process called gluconeogenesis. Metformin may also work by increasing the ability of skeletal 
muscle to remove glucose from the bloodstream and use it for energy. 
● Nicotinamide Adenine Dinucleotide (NAD+): NAD+ is a molecule found in every cell that plays a key 

 
Protocol Number: ALRx011v3 
                    Date Amended: December 3, 2025 
Approval Number: IRCM-2025-437             
 Continuing Review Date: September 16, 2026 
role in energy production, DNA repair, and maintaining healthy brain function. Increasing NAD+ levels, 
often through supplements or other interventions, may help slow aging, improve energy, and promote 
overall health. 
● Glutathione (GSH): Glutathione is an antioxidant that helps protect cells from oxidative stress and 
damage. It also plays a key role in detoxifying the body, supporting the immune system, and reducing 
inflammation. Boosting glutathione levels is often used for improving overall health and longevity. 
● Infinite Premium Longevity Support: a nutraceutical formulation designed to enhance cellular health and 
mitigate age-related physiological decline. The ingredients include Calcium Alpha-Ketoglutarate, 
Quercetin, Glucosamine, Carnosine, Pterostilbene, Astaxanthin, and Curcumin. 
● Placebo/control: Vitamin C and Vitamin E supplements 
Interventions:  
You will be randomized into one of the following arms: 
● Arm 1 Multi-Therapy: B12, LDN, NAD+, and Metformin 
● Arm 2 - Comprehensive Therapy: LDR, LDN, B12, Metformin, NAD+, GSH, and Infinite Premium 
Longevity Support 
● Control: Vitamin C and E supplements 
Specimen Collection: 
 
● Commercially-available mail-based kits for advanced longevity biomarkers (Edifice Health's iAge test 
and iollo) will be completed at-home and returned by mail. The study staff will be available for 
assistance.  
● Bloodwork will be completed for all participants at the Quest Diagnostics or LabCorp facility nearest to 
them (identified with the assistance of study staff).  
Questionnaires/Assessments: 
 
● Immune Status Questionnaire (ISQ) 
● SF-36 Quality of Life (SF-36 QoL) 
● Rapid Assessment of Physical Activity (RAPA) questionnaire 
● Sleep Quality Survey (SQS) 
● Creyos Cognitive Testing 
Imaging and Testing:  
● DXA Scans 
● VO2 Max tests (formal test administered at a facility and with Oura ring estimate) 
Wearables: 
● Oura Ring (to measure general health indicators such as sleep, physical activity, heart rate, etc.) 
Additional: 
● A digital guided meditation program 
● A guided at-home exercise program 
Risks 
What are the risks of participating in the research study? 

 
Protocol Number: ALRx011v3 
                    Date Amended: December 3, 2025 
Approval Number: IRCM-2025-437             
 Continuing Review Date: September 16, 2026 
● Interventions: The potential risks of these interventions vary but may include common side effects like 
nausea, headaches, and digestive issues. Some, like low-dose rapamycin can increase the risk of 
infections or cause skin discoloration and dizziness. Others, such as metformin, may lead to GI 
discomfort, such as stomach cramps, diarrhea, nausea, bloating or constipation. Glutathione and NAD+ 
supplements can cause mild discomfort like bloating or fatigue. In some cases, these treatments may 
interact with other medications or have more serious effects. These risks have been deemed minimal 
and will be monitored closely by the research team. You will be instructed to notify the research team of 
side-effects and adverse events. 
● Blood draw: The insertion of the needle to draw blood can be painful; however, the discomfort is brief. 
For most people, needle punctures to get blood samples do not cause any serious problems; however, 
they may cause bleeding, bruising, discomfort, infections, dizziness, or fainting. 
● Questionnaire/Survey Research: Some of the questions we will ask you as part of this study may make 
you feel uncomfortable. You may refuse to answer any of the questions and you may take a break at 
any time during the study. You may stop your participation in this study at any time. 
● Unknown Risks: There may be risks or side effects related to the study interventions that are unknown 
at this time. You will be notified of any significant new findings that become known that may affect your 
willingness to continue in the study. 
How will my data/specimens be used?  
Your data/samples/images may be sent outside of the AgelessRx for research purposes only. We will allow 
data access, use, and material transfers to XPRIZE as needed for judging and future analyses. Any personal 
information that could identify you will be removed before they are shared.  
Collection of biospecimens by third-party testing vendors will be treated in accordance with the procedures set 
up by vendors for maintaining and storing samples and sample data. While no genetic information is intended 
to be collected in this study, best efforts will be made to minimize exposure of any associated PHI and 
identifying biological information in perpetuity. A sample containing the participant's DNA may be archived and 
it could be analyzed by Whole Genome Sequencing, so the participant's DNA gene sequence may be known.  
Additional information on the specific sample handling practices of each third-party vendor used for testing in 
this study is available upon request from the AgelessRx research staff.  
Confidentiality Risks 
There is a small, but non-zero potential risk of loss of confidentiality of your data. Every effort will be made to 
keep your information confidential as it will be stored in a secure database and only accessible to the research 
study team. Personal information will be closely protected, and you will not be identifiable in any publication 
resulting from this study.  
Your medical information is unique to you. There is a small, but non-zero risk that someone outside of the 
research study could get access to your study records or trace information in a database back to you. While 
the chance that someone could access and misuse your information is believed to currently be very small, it is 
possible that the risk may increase in the future as people find new ways to access information.  
What are possible benefits of participating in the research? 
Participation in this study may help to improve your healthspan and longevity, but it is also possible that your 
health may worsen. There is no guarantee that you will personally benefit by participating in this research 
study. Your participation in this study may provide information that may help others improve their healthspan 
and lifespan in the future. 
Are there any costs to you if you participate in this study? 

 
Protocol Number: ALRx011v3 
                    Date Amended: December 3, 2025 
Approval Number: IRCM-2025-437             
 Continuing Review Date: September 16, 2026 
There is no cost to you to be in this research study.  
 
Authorization to Use/Disclose Protected Health Information 
Study results may be shared in medical journals, at scientific meetings, and in other mediums without your 
identifying information. Your records will be confidential and your identity will not be shared in medical journals, 
at scientific meetings, and in other mediums without your express consent.  
AgelessRx has rules and procedures to protect information about you. Federal and State laws also protect 
your privacy. The research team working on the study will collect information about you. This includes your 
health information, data collected for this research study and personal identifying information including your 
name, address, date of birth and other identifying information.  
Generally, only people on the research team will know your identity and that you are in the research study.  
However, sometimes other people at AgelessRx may have access to your information on a need-to-know 
basis. These include people who review research studies including the Institutional Review Board and 
Research Compliance, their staff, lawyers, or other AgelessRx staff.  
People outside AgelessRx may see your information for this study. Examples include government groups 
(such as the Food and Drug Administration), safety monitors, other hospitals in the study and the sponsor of 
the research and their agents. AgelessRx will do our best to ensure your information is kept confidential and 
that only the health information which is minimally required to conduct the study is used or disclosed to people 
outside AgelessRx. 
You do not have to give this permission to use and give out your information; however you will not be able to 
participate in this research study without providing this permission by signing this consent form. The use and 
disclosure of your information has no expiration date.  
You may cancel your permission to use and disclose your information at any time in writing. If you do cancel 
your permission to use and disclose your information, your participation in this study will end and no further 
information about you will be collected. Your cancellation would not affect information already collected in the 
study. 
 
Clinical Trials Language 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov. This Website will not include 
information that can identify you. At most, the Website will include a summary of the results. You can search 
the Website at any time. 
 
Who do you call if you have any questions or problems?  
If you have any questions or concerns about the research, or develop a research-related problem, you should 
contact the research team directly at research@agelessrx.com or (650) 503-1889, press 1 to leave a 
voicemail. If you have questions about your rights as a research participant, you should contact the 
Institutional Review Board. 
What are your rights as a research participant? 
Taking part in this study is voluntary. You will be told of any new, relevant information from the research that 
may affect your health, welfare, or willingness to continue in this study. You may choose not to take part or 
may leave the study at any time. Withdrawing from the study will not result in any penalty or loss of benefits to 

 
Protocol Number: ALRx011v3 
                    Date Amended: December 3, 2025 
Approval Number: IRCM-2025-437             
 Continuing Review Date: September 16, 2026 
which you are entitled. If you decide to withdraw from the study you should discuss with your study doctor 
your decision to ensure a safe withdrawal. 
If you leave the study early, AgelessRx may use your health information that has already been collected in 
accordance with the processes outlined above if the information is needed for this study or any follow-up 
activities.  
 
 
 
Signatures 
Statement of Participant 
I have read and have had verbally explained to me the above information and have had all my questions 
answered to my satisfaction. I understand that my participation is voluntary and that I may stop my 
participation in the study at any time. I understand that a copy of this consent will be provided to me.  
Should I wish to contact an impartial third party not associated with this study, I may contact James P. Faber, 
secretary of the Institutional Review Board (IRB) of the Institute of Regenerative and Cellular Medicine 
(IRCM), which reviewed this study for ethical compliance: jpfaber@ircm.org or (786) 271-2156. 
By signing below, I confirm that I have read and understood the information provided, have had the 
opportunity to ask questions, and agree to participate in this study.  
 
 
 
 
Participant Signature: _______________________ Date: ______________________  
 
 
Principal Investigator Signature:
Date: __11/13/2025__________________