Kittle's only trip a mile high came Sept. 25, when the Niners played at the Denver Broncos. His recollection of how the altitude in Denver -- elevation 5,195 feet -- affected him was that he was "mildly out of breath," but he also noted he was still working his way back into football shape from a groin injury.
With the Niners set to travel to Mexico City -- elevation 7,503 feet -- for a Monday Night Football matchup with the Arizona Cardinals at Estadio Azteca (8:15 p.m. ET, ESPN/ESPN+/ABC), Kittle did what he often does when he has a question: He called Kansas City Chiefs tight end Travis Kelce for advice.
Kelce plays yearly games in Denver and had 92 yards and a touchdown against the Los Angeles Chargers in 2019 when they played in Mexico City.
"He said the altitude was just difficult," Kittle said. "He plays in Denver every year, too, and so he said it was definitely a big change from what they've played in before ... I know it's gonna be something."
Kittle wasn't the only 49er expecting altitude to be a challenge. In fact, as soon as the NFL announced the Mexico City matchup in the spring, the 49ers performance staff, led by head of player health and performance Ben Peterson, began looking at options to try to mitigate the altitude's effects.
There have been 10 NFL games played in Mexico City, four in the regular season. The teams that have preceded the Niners and Cardinals have subscribed to two schools of thought when it comes to altitude acclimation: get into it as early as possible or as late as possible.
In some ways, Monday night's game will be as much a battle of scientific philosophies as football ones.
On Peterson's recommendation, the Niners chose the early route, arriving in Colorado on Tuesday to practice Thursday, Friday and Saturday at the United States Air Force Academy -- elevation 6,621 feet at the football stadium -- and acclimate.
The 49ers will leave for Mexico City on Sunday afternoon, hoping that time spent in Colorado will give them an edge.
"You want to practice in that altitude because the more days you spend in it, the more your body gets used to it," Shanahan said. "So, hopefully it'll make it easier for us Monday night."
The Cardinals opted for the other approach, as strength and conditioning coach Buddy Morris decided on a modified program involving stationary bikes and elevation masks the Cardinals can use at their training facility. They will arrive in Mexico City on Saturday.
"We felt like the program we could set up here for all the altitude training was really good and wouldn't disrupt our routine," Cardinals coach Kliff Kingsbury said. "They've been at it for the last two or three weeks. All of our guys have been on it trying to prep for that, but I know it'll be a challenge either way whether you do that or not."
Acclimating to altitude isn't as simple as just spending time at higher elevations, however.
According to Inigo San Millan, an associate research professor in the department of Physiology and Nutrition and the school of medicine at the University of Colorado in Colorado Springs, it takes about three weeks to fully adapt to the altitude. That doesn't mean that the 49ers can't gain an advantage by spending the week in Colorado prior to Mexico City.
"It's not enough time to fully adapt to altitude," San Millan said. "It's enough time to at least not suffer the effects from altitude."
Getting even semi-acclimated can happen only if the 49ers take the proper steps, according to San Millan. He has worked with many athletes, including Olympic medalists and Tour De France winners, for 27 years while studying the effects of altitude on athletic performance.
As San Millan explains it, the issue with acclimation isn't about the amount of oxygen in the air. The real problem comes from barometric pressure.
Under normal circumstances at sea level, the weight of the atmosphere can help press oxygen into the bloodstream, which feeds muscles. In a place like Mexico City, the barometric pressure is lower, which results in oxygen saturation dropping.
Athletes can find it difficult to breathe at altitude because of that decreased oxygen level in their bloodstream. In his research, San Millan and others believe that for every 1,000 feet above sea level, someone loses 2% of their ability to utilize oxygen and the ensuing time before feeling exhaustion is roughly 4% faster.
Which means that in Mexico City, the Niners and Cardinals will be able to consume about 14% less oxygen and reach exhaustion about 28% faster than at sea level.
The body has built-in adaptations to help in the form of an increasing amount of red blood cells, which San Millan calls the "taxi of oxygen," so that there are enough to deliver the right amount of oxygen to the necessary tissues in the body.
The key for the Niners to make it work, however, is to not push too hard in that one week. San Millan said that overtraining is typical in athletes trying to adapt to altitude but that they should actually spend the first week doing little physical activity.
Shanahan said Monday that the Niners wouldn't be making significant changes to how they practice, but they didn't practice until Thursday despite arriving in Colorado on Tuesday.
"That's where there's a double-edged sword to go for such a short period of time," San Millan said. "In one week, you can adapt to some extent. But again, looking at the possible side effects you're gonna be seeing players who are not gonna sleep well, they're not going to maybe recover well. The training needs to be significantly altered."
Beyond the training regimen, two other key factors for altitude adaptation are sleep and nutrition.
San Millan said when he works with athletes, he implements an altered nutrition plan in the first week which involves adding about 30% more carbohydrates and protein to their diets in order to maintain energy levels.
The challenge for the Niners comes in not only ensuring they're doing those things correctly but managing so many players at the same time. While San Millan can track four or five athletes at a time by doing a blood analysis every five to seven days, that task is more difficult for a 53-man roster.
As for sleep and nutrition, Kittle said each room at The Broadmoor, the team hotel, has a humidifier to moisten the air and there's been an emphasis on drinking plenty of water and eating "as much as you can."
This week, the Niners also got an idea of how a football's velocity can increase in less dense air, something wideout Brandon Aiyuk noted on Thursday.
The returns from players this week have been that the altitude wasn't "too bad" on the practice field, though it was felt most when "stringing plays together," which means long drives on either side could be tough to overcome on Monday.
For their part, the Niners seem happy with the decision to get a taste of the altitude in Colorado, even if it's been paired with frigid temperatures and snow.
"It's good that we're out here doing it now so when we get to Monday it's not a shock," linebacker Fred Warner said.